US12059413B2 - Methods of inhibiting viruses using compositions targeting TSG101-ubiquitin interaction - Google Patents
Methods of inhibiting viruses using compositions targeting TSG101-ubiquitin interaction Download PDFInfo
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- US12059413B2 US12059413B2 US16/342,695 US201716342695A US12059413B2 US 12059413 B2 US12059413 B2 US 12059413B2 US 201716342695 A US201716342695 A US 201716342695A US 12059413 B2 US12059413 B2 US 12059413B2
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
- G01N33/56983—Viruses
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
- G01N33/56983—Viruses
- G01N33/56988—HIV or HTLV
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- Polyubiquitylation serves as a signal triggering internalization of cell-surface proteins [Dupre et al (2004), Ubiquitin and endocytic internalization in yeast and animal cells. Biochim Biophys Acta. 1695:89-111].
- these normal signaling events oppose some steps important for pathogen replication, e.g., the process of enveloped virus egress from the plasma membrane of infected cells or budding of some viral intermediates from the nucleus into the cytoplasm.
- viruses including the human immunodeficiency virus (HIV-1), engage cellular machinery to facilitate exit from the cell periphery but, as this same machinery functions in cell protein internalization, the virus must employ additional measures to prevent its proteins from being treated like cellular cargo.
- HIV-1 human immunodeficiency virus
- the present invention provides a method of inhibiting release of a virus from a cell, comprising contacting the cell with a compound that binds an ubiquitin E2 variant (UEV) domain of a cellular polypeptide, or fragment thereof, with an affinity sufficient to inhibit or disrupt the binding of the cellular polypeptide, or fragment thereof, to ubiquitin.
- a compound that binds an ubiquitin E2 variant (UEV) domain of a cellular polypeptide, or fragment thereof with an affinity sufficient to inhibit or disrupt the binding of the cellular polypeptide, or fragment thereof, to ubiquitin.
- the present invention also provides a method of treating a patient infected with a virus, comprising administering to the patient a compound which binds to the UEV domain Ub-binding pocket of a cellular polypeptide in an amount effective to inhibit the binding of the cellular polypeptide to ubiquitin.
- the present invention also provides a method for identifying a compound that binds a UEV domain Ub-binding pocket of a cellular polypeptide with an affinity sufficient to inhibit or disrupt formation of an associative complex in a cell, comprising the steps of:
- FIG. 1 Tsg101 ubiquitin E2 variant (UEV) domain complexed to ubiquitin.
- Highlighted (arrow) is the buried position of the ubiquitin residue Lys48.
- FIG. 2 Compound-induced unwanted polyubiquitination.
- ubiquitin moieties are linked as a result of isopeptide formation between Lys48 in the acceptor Ub and the C-terminus of an incoming Ub.
- the last Ub in the chain has its Lys48 solvent exposed and available to the next incoming Ub.
- the illustration shows unwanted K48-linked polyubiquitination resulting from compound binding and the ensuing interference with Ub binding in the pocket within the Tsg101 UEV domain.
- FIG. 3 Inhibition of HIV-1 virus production.
- Virus production was measured from the amount of virus detected in the tissue culture media at the end of a 24-hr treatment period.
- Top semi-quantitation by immunoblotting.
- Virus particles in filtered tissue culture media were isolated by sucrose cushioning and electrophoresis on SDS polyacrylamide gel. Proteins separated on the gel were blotted onto nitrocellulose and the blot probed with anti-p24 antibody revealing the mature p24 protein as the major p24-containing viral protein on the blot.
- Middle quantitation analysis by ELISA.
- Proteins in tissue culture media were denatured and total p24 protein level quantitated using p24-capture ELISA assay. Assay values were normalized to that of the DMSO carrier control. Bottom, quantitation of specific virus infectivity. Tissue culture volumes calculated to contain equivalent amounts of viral particles were used to infect a monolayer of MAGI cells in a single round HIV-I replication assay. Assay values were normalized to that of the DMSO carrier control.
- FIG. 4 A-E Binding of compound to Tsg101 UEV domain.
- Panels A, C, and E provide an illustration of regions significantly perturbed (darkened regions) in the Tsg101 UEV domain surface (white; from PDB ID: IKPP; Pornillos et al. EMBO J, 2002) following binding of compound (perturbed regions in red), PT AP (perturbed regions shown as darker region) and Ub (perturbed regions shown as darker region).
- Panels B, D, F Large (gray bars) and small (black bars) NMR chemical shifts by residues in the Tsg101 UEV domain induced by incubation with compound (red); PTAP (panel D); and Ub (panel F).
- Panel G 200 structures of the compound-Tsg101 UEV complex were calculated of which the twenty lowest in energy are shown in ribbon, with the compound in lines.
- Panel H Enlarged depiction of the lowest energy complex structure showing UEV domain region, compound (darker region) and binding site residues shown as spheres and sticks. Inset: illustration of disulfide adduct formed by compound.
- FIG. 5 A-D Covalent binding to Tsg101 residue C73.
- FIG. 5 A compound activation to reactive sulfenamide (Shin & Kim, J Neurogastroenterol Motil 2013). Compound (i) is converted through acid catalysis to intermediates sulfenic acid (ii) and sulfenamide (iii) with reactivity to Cys residue sulfides to yield a covalently attached compound (iv) in the compound-Tsg101 UEV domain complex.
- FIG. 5 B loss of inhibitory effect of compound when activation is allowed to takes place prior to addition of compound to cells.
- FIG. 5 C NMR evidence for disulfide bond formation with Tsg101 UEV domain residue Cys73. Chemical shift of residues C73, L74, 186 and C87 of Tsg101 UEV domain without ( ⁇ ) and with (+) compound. The C ⁇ peak for C73 changed from 29.27 to 46.69 ppm upon addition of compound, indicating oxidation (formation of a covalent disulfide bond), whereas the C ⁇ peak for C87 remained unchanged.
- FIG. 5 C NMR evidence for disulfide bond formation with Tsg101 UEV domain residue Cys73. Chemical shift of residues C73, L74, 186 and C87 of Tsg101 UEV domain without ( ⁇ ) and with (+) compound. The C ⁇ peak for C73 changed from 29.27 to 46.69 ppm upon addition of compound, indicating oxidation (formation of a covalent disulfide bond), whereas the C ⁇ peak for C87 remained unchanged.
- FIG. 5 C NMR evidence for disulfide bond formation with Tsg
- FIG. 6 A-B Proposed rabeprazole derivatives.
- FIG. 6 A Rabeprazole (center)—related compounds referred to as prazoles.
- FIG. 6 B Residues perturbed by bound compound superimposed on ribbon drawing of the Tsg101 UEV domain complexed with the PEPTAPPEE peptide delived from PDB structure 1M4P (Pornillos et al Nat Struct Biol, 2002). UEV residue Cys73 with which the compound forms a disulfide-linked adduct is shown. Residues perturbed by the bound compound are shown in with darker intensity reflecting extent of perturbation.
- FIG. 7 Inhibitory effect of compound on Alix-driven budding of an HIV-1 Gag mutant.
- P7L-Gag budding is directed by Alix which binds to the LYXP motif located several residues downstream of the PTAP motif. Bar graph, quantitation of VLP production normalized to that of mock-treated control.
- FIG. 8 Inhibitory effect of compound on Nedd4-driven budding of Avian Sarcoma Virus.
- the PY motif recruits the E3 ligase, Nedd4.
- Bar graph quantitation of VLP production normalized to that of mock-treated control.
- FIG. 9 See FIG. 5 B above.
- FIG. 10 A- 10 C compare the antiviral effect of Rabeprazole to prazoles.
- FIG. 11 A Comparison to time to formation of active sulfenamide compound.
- FIG. 11 B Time-dependence of anti-viral impact.
- FIG. 12 Comparison of prazoles “fit” within Tsg101-UEV structure, relative to positions of Ub- and PTAP-binding pockets.
- FIG. 13 A NMR and fluorescence perturbances indicate that all of the compounds (tenatoprazole, esomeprazole, pantoprazole, lansoprazole, and rabeprazole) bind to residue C73. Pantoprazole has additional binding at C87.
- FIG. 13 B TSG101 binding of prazole compounds. Melting curves of TSG101 with various prazole compounds assayed by relative fluorescence (RFU) shift. Two control compounds, K21 and N20, had no effect at 40 ⁇ M on the Tsg101 melting curve.
- FIG. 14 A-F The ubiquitin E2 variant (UEV) domain of Tsg101 was purified by attaching it to an N-terminal His tag with a Tobacco Etch Virus nuclear-inclusion-a endopeptidase (TEV) cleavage site and isolating the tagged protein through two consecutive nickel columns. The first nickel column bound the Tsg101 with the His tag. Following cleavage of the His tag, Tsg101 flowed straight through the second column, removing any impurities from the cell lysate that also bound to the column in step 1, as well as the TEV protease enzyme.
- A-C describe the purification; D and E describe the addition of the N16 ligand; panel F shows binding of N16 (top) and F15 (bottom) to the purified Tsg101 UEV fragment.
- N16 Dose-dependence of Tsg101 normalized melting curves for N16 (top) and F15 (bottom). At same concentration, N16 shifts the melting curve to a greater extent to the left than F15. Specifically, at 20 uM, N16 caused a 12 degree Tm shift while F15 gave rise a 5 degree Tm shift. This difference correlated with the potency observed in the cell-based assay.
- the plot for N16 contains two control compounds, K21 and N20, which have no effect at 40 uM on the Tsg101 melting curve.
- FIG. 15 A-D N16 inhibits HIV-1 NL4-3 and Gag VLP production.
- FIG. 16 A-B N16 inhibition of HIV-1 transmission in a spreading infection in Jurkat cells.
- control media containing DMSO
- virus replication peaked at day 11; in the presence of N16, production peaked at 13 days.
- Cells were monitoring periodically for viability by Trypan Blue assay. To test their ability to produce virus after this sustained exposure, at day 15 the N16-treated cells were washed, fresh media without inhibitor was added and the cells were incubated 4 days longer (to day 19). The supernatant was collected, the cells were washed again and then incubated for another 4 days in media with inhibitor, adding fresh inhibitor daily. The final supernatant was collected on day 23. The virus level surged by 10-fold when N16 was removed indicating that the observed inhibition was not attributed to irreversible cell toxicity.
- FIG. 17 A-C A) Effect of N16 on Gag VLP production and Gag steady-state in 293T and HieLa cells. Top, Cells treated with 0, 50, 100, and 150 ⁇ M N16 were transfected with DNA encoding Gag-HA. At the end of the treatment period, tissue culture media was removed for VLP isolation. Cells were suspended in lysis buffer. Blots were probed for Gag-HA and actin. Bottom, Quantitative analysis. Relative effects of N16 on VLP and SI Gag. B) Effect of ‘in cellulo’ bortezomib on N16-mediated interference with VLP production and Gag steady-state. Top, Schematic diagram summarizing experimental protocol.
- Panel C Effect of ‘ex cellulo’ treatment with proteasome inhibitor MG132 and NEM on N16-mediated interference with Gag steady-state. Top, Cells treated at the indicated concentration were transfected with DNA encoding Gag-HA. At the end of the treatment period, tissue culture media was removed for VLP isolation.
- FIG. 18 A-C Localization of endogenous Tsg101+/ ⁇ N16.
- tissue culture media was removed from 10 cm plates of 293T cells and replaced with media containing either 50 uM N16 or the DMSO vehicle. After a 24 hr treatment period, cells were harvested and suspended in hypotonic buffer, Dounce homogenized and the homogenate subjected to differential centrifugation to obtain subcellular fractions that we have characterized in Goff et al.
- FIG. 19 A-F N16 (50 ⁇ M) prevents co-localization of Gag and Tsg101 on the plasma membrane.
- A-E Fluorescence microscopy images of cells that co-express Tsg101-Myc alone or GagWT-GFP and Tsg101-Myc. Cells grown on coverslips were co-transfected with DNA encoding Tsg101-Myc (A) or Tsg101-Myc and GagWT-GFP (B, D and E) or GagP7L-GFP (C) and treated with F15 (D) or N16 (E).
- Tsg101-Myc in cells treated with DMSO carrier (top) or N16 (bottom).
- B-E Top panels, show signal from Gag-GFP; middle panels, images showing Tsg101-Myc signal; bottom panels, merged images showing signals from Gag-GFP and Tsg101-Myc. Boxes frame a region of the plasma membrane.
- FIG. 20 A-C N16 inhibition is virus-specific.
- FIG. 21 A-B N16 suppresses the inhibitory effect of fusing DUb to Gag.
- A) 293T cells were transfected with DNA encoding Gag or Gag-DUb. After 24 hr, tissue culture media was removed for VLP isolation and cell lysates were prepared. Top, Western blot analysis of Gag in cushioned VLP samples; Middle, Gag and actin in cell lysates; Bottom, Quantitative analysis of VLP release efficiency normalized to the WT Gag control (Gag and Gag-DUb differed in sample size in order to yield visible signal); B) Effect of N16 on Gag and GagDUb VLP production. Top, Western blot analysis; Triplicate samples are shown to demonstrate reproducibility. Bottom, Quantitative analysis of VLP production (left), lysate Gag (center) and VLP release efficiency (right) normalized to the mock-treated control. Number of independent assays: n 3
- FIG. 22 A-H Solution NMR reveals that N16 interferes with Ub binding to Tsg101 UEV domain.
- PDB ID: 1KPP surface representation in white
- E Gag PTAP peptide
- G ubiquitin
- FIG. 23 HSQC spectra of the Tsg101 UEV domain in the presence and absence of N16. 15N-Tsg101 UEV HSQC spectrum in the absence and presence of N16 (excess N16 and DMSO removed by ultrafiltration). The ten largest chemical shift perturbations are highlighted with residue numbers. Stars indicate the location of residues C73 and K90, which are broadened in the presence of N16.
- FIG. 24 A-B HSQC spectra of the Tsg101 UEV domain in complex with the PTAP peptide, in the presence and absence of N16.
- FIG. 25 A-B HSQC spectra of the Tsg101 UEV domain in complex with ubiquitin, in the presence and absence of N16.
- FIG. 26 A-D N16 binds covalently to C73 in the Tsg101 UEV domain.
- N16 (i) is converted to intermediates sulfenic acid (ii) and sulfenamide (iii) through acid catalysis to yield a covalently attached N16-Tsg101 UEV complex (iv).
- FIG. 27 A-C Effect of N-Acetyl Cysteine (NAC) on N16-mediated inhibition of VLP production and intracellular Gag accumulation.
- NAC N-Acetyl Cysteine
- FIG. 28 A-C N16 inhibition is suppressed by replacing endogenous Tsg101 with the Tsg101-C73A mutant.
- Tissue culture media was collected 24 hr post-DNA transfection, filtered and examined for virus production.
- the present invention provides a method of inhibiting release of a virus from a cell, comprising contacting the cell with a compound that binds an ubiquitin E2 variant (UEV) domain of a cellular polypeptide, or fragment thereof, with an affinity sufficient to inhibit or disrupt the binding of the cellular polypeptide, or fragment thereof, to ubiquitin.
- a compound that binds an ubiquitin E2 variant (UEV) domain of a cellular polypeptide, or fragment thereof with an affinity sufficient to inhibit or disrupt the binding of the cellular polypeptide, or fragment thereof, to ubiquitin.
- the compound binds the UEV domain of the cellular polypeptide, or fragment thereof, with an affinity sufficient to inhibit or disrupt formation of an associative complex comprising the cellular polypeptide, or fragment thereof, that includes the UEV domain Ub-binding pocket, and:
- the associative complex comprises a) the cellular polypeptide, or fragment thereof, that includes the UEV domain Ub-binding pocket and b) an ubiquitin-modified cellular polypeptide for the virus' production other than the cellular polypeptide that includes the UEV domain Ub-binding pocket, or fragment thereof, that is capable of binding said UEV domain Ub-binding pocket.
- the associative complex further comprises a) an ubiquitin-modified polypeptide of the virus, or fragment thereof, that is capable of binding said UEV domain Ub-binding pocket.
- the compound disrupts at least 50% of the binding of the UEV domain of the cellular polypeptide, or fragment thereof, to ubiquitin.
- the compound is present at a concentration of 1-200 ⁇ M, preferably the compound is present at a concentration of 10-150 ⁇ M, more preferably the compound is present at a concentration of 15-100 ⁇ M, even more preferably the compound is present at a concentration of about 25 ⁇ M.
- the present invention also provides a method of treating a patient infected with a virus, comprising administering to the patient a compound which binds to the UEV domain Ub-binding pocket of a cellular polypeptide in an amount effective to inhibit the binding of the cellular polypeptide to ubiquitin.
- the cellular polypeptide that includes the UEV domain Ub-binding pocket is TSG101.
- the virus is an enveloped virus.
- the virus is not known to have an L-domain motif, wherein the L-domain motif is any one of PPX n Y, PTAP or LYPX n L.
- the virus is at least one of Hepatitis C virus, Human Papillomavirus, Herpes Simplex virus type 1, Dengue virus, Japanese Encephalitis virus, Human Parainfluenzavirus Type 1, or Epstein Barr Virus.
- the virus is known to have an L-domain motif, wherein the L-domain motif is any one of PPX n Y, PTAP or LYPX n L.
- the virus is at least one of Human Immunodeficiency virus type 1 (HIV-1), Influenza virus or Human cytomegalovirus.
- HIV-1 Human Immunodeficiency virus type 1
- Influenza virus Human cytomegalovirus
- the virus is at least one of Zika virus, Dengue virus, Epstein Barr virus, Influenza virus or Measles virus.
- the virus is at least one of Human Immunodeficiency virus type 1 (HIV-1), Human Papillomavirus or Herpes Simplex virus type 1.
- HIV-1 Human Immunodeficiency virus type 1
- Human Papillomavirus Human Papillomavirus
- Herpes Simplex virus type 1 Human Immunodeficiency virus type 1
- the virus is at least one of Mopeia virus, Tacaribe virus, Human Parainfluenzavirus Type 1, Dengue virus, Hepatitis C virus, Japanese Encephalitis virus, Herpes Simplex virus, Epstein-Barr virus and Human Cytomegalovirus.
- the virus is not an enveloped virus.
- the virus is at least one of Polio virus or Human Papilloma virus.
- the compound is:
- the compound is:
- the compound has the structure:
- the compound has the structure:
- the cell is a human cell.
- the cell is a plant cell.
- the virus is at least one of Tomato Bushy Stunt virus or Brome mosaic virus.
- the present invention also provides a method for identifying a compound that binds a UEV domain Ub-binding pocket of a cellular polypeptide with an affinity sufficient to inhibit or disrupt formation of an associative complex in a cell, comprising the steps of:
- the present invention relates generally to anti-viral therapeutics that target a factor critical for production of a broad spectrum of viral pathogens, but which will not induce formation of resistant viruses, and in particular, to methods of inhibiting animal viruses using compositions targeting TSG 101-ubiquitin interaction.
- Some formulations of the therapeutics are deliverable as agents that have already been demonstrated to be safe, well-tolerated, and market acceptable as drugs.
- Advantages of the embodiments of the invention described herein include ‘First-in-class” anti-TSG101 therapeutics that (1) minimize emergence of drug-resistance by targeting a highly conserved cell-encoded, rather than viral-encoded protein.
- the use of virus-encoded gene products as targets invariably selects for drug-resistant variants.
- a further advantage includes delivery of the anti-viral agents as long-acting and sustained release formulations that are anticipated to reduce current problems arising from lack of patient adherence to therapeutic regimens.
- the formulations in use are already known to be safe, well-tolerated, and market acceptable as drugs for a different indication.
- An additional advantage includes the fact that the therapeutic composition is highly specific for the target as required by the virus rather than host.
- the anti-viral therapeutic is broad spectrum as many pathogens require the Tsg101 protein to mediate trafficking functions. (6) Moreover, efficacy does not require direct binding of a viral-encoded protein to the targeted cellular protein. (7) The therapeutic can be presented as a pro-drug, i.e., requiring local formation of an active derivative, thereby reducing possible off-target encounters.
- a method for inhibiting a mechanism used by the enveloped virus HIV-1 to prevent internalization and promote its release from the cell.
- This method includes contacting a cell with a compound having an antiviral activity, said antiviral activity comprises: (i) inhibiting formation of an associative complex; or (ii) weakening formation of an associative complex, wherein the associative complex comprises a mono- or di-ubiquitin (Ub) moiety on any protein, viral-encoded or cellular-encoded, that is required for production of released infectious virus particles and TSG101 or fragment thereof, capable of binding the Ub moiety on a viral or cellular protein.
- Ub mono- or di-ubiquitin
- the mechanism used by the virus to prevent internalization is based on the fact that TSG101 is an intrinsically inactive E2 enzyme and, as such, addition of another Ub moiety to the Ub moiety on the viral/cellular protein to create a polyUb signal is prevented. See FIG. 1 .
- the antiviral activity is based on the novel understanding that compounds having the property specified within this disclosure disrupt or inhibit formation of the TSG101 complex with Ub, thereby promoting the undesirable polyUb events that signal viral protein internalization. See FIG. 2 .
- the effect of the viral protein internalization is inhibition of viral particle release from the cell (see FIG. 3 , top and middle panels) and reduction of virus infectivity (see FIG. 3 , bottom panel).
- a key property conferring the compound with antiviral activity is the ability to form a reactive sulfide moiety within the cellular milieu at a site where the virus replicates that can attack specific Cys residues in TSG101, namely, Cys73 and/or Cys87 within the Ub-E2-variant (UEV) domain of the TSG101 protein (depending on the specific compound employed). See FIG. 4 . W7S and F88 are also important contacts.
- FIG. 5 A illustrates formation of the reactive sulfide moiety using a related compound.
- FIG. 5 B illustrates that the antiviral activity requires intracellular formation of the reactive sulfide: inducing formation prior to cell uptake, ablates antiviral activity.
- FIG. 5 A illustrates formation of the reactive sulfide moiety using a related compound.
- FIG. 5 B illustrates that the antiviral activity requires intracellular formation of the reactive sulfide: inducing formation prior to cell uptake, ablates antiviral activity.
- FIG. 5 C illustrates that the specific target residue within TSG101 for the compound illustrated in FIG. 5 A is Cys73, as indicated by its perturbation when a compound capable of forming the reactive group is added; a nearby Cys residue is not disturbed.
- FIG. 5 D illustrates that the Cys73 residue in TSG101 is also the specific target of the compound inside the cell as indicated by failure to prevent co-localization of Gag (green signal) and TSG101 (red signal) when Ala is substituted for Cys73 but not when Ala is substituted for Cys87.
- the L domain motif (Pro-Thr-Ala-Pro or PTAP) in the HIV-1 Gag protein can bind a PTAP-binding pocket in the UEV domain of TSG101.
- the antiviral property described herein affects some residues involved in L domain recognition but does not require or target the intact L domain motif in the Gag protein for the interaction with TSG101. [e.g., Kim et al (2011) Elucidation of New Binding Interactions with the Human TSG101 Protein Using Modified HIV-1 Gag-p6 Derived Peptide Ligands ACS Med. Chem. Lett. 2, 337-341 targets the motif itself].
- the enveloped viruses to which the herein specified antiviral activity may apply can be Zika virus, Dengue virus, Human Immunodeficiency virus, Ebola virus, certain Hepatitis viruses, Herpes Simplex virus-1 and/or -2, Epstein-Barr virus, Mumps, Measles, Influenza virus, Vesicular Stomatitis virus, and viruses related to the above named groups.
- FIG. 6 B shows the L domain motif contacts relative to the location of TSG101-Cys 73 that is target of compounds in panel 6A.
- the UEV domain of TSG101 in complex with the PEPTAPPEE peptide from the late domain of HIV-1 p6 (Gag) is derived from PDB structure 1M4P (Pornillos et al (2002) Nat Struct Biol 9, 812-817). Residues important for ubiquitin complexation are shown in sticks (D43, N45, D46 and F88) (PDB ID: ISlQ, Sundquist et al (2004) Molec Cell 13, 783-789).
- the evidence for covalent binding to cysteine 73 is that mass spectrometry of the UEV domain of TSG101 in the presence and absence of tenatoprazole indicated two things: (1), that Tenatoprazole binds to TSG101 in a covalent manner; and (2), that there is a 1:1 binding ratio of tenatoprazole to TSG101. It is noted that NMR spectroscopy is capable of revealing sites of covalent attachment by comparison of the spectra before and after addition of the ligand.
- cysteine 73 After addition of tenatoprazole to the UEV domain of TSG101, cysteine 73 showed a large change in the C_beta chemical shift characteristic of covalent disulfide bond formation, whereas the C_beta of cysteine 87 did not. Putting the data together, tenatoprazole binds covalently via a disulfide bond to cysteine 73 of the UEV domain of TSG101.
- the tenatoprazole binding site therefore overlaps with both the PTAP binding site and that of Ub. See FIG. 4 . Perturbations line up with the Pro 7 and Pro 10 contacts but the Thr 8 or Ala 9 contacts were not disturbed. Threonine 58 is the key. It has a large chemical shift change when N16 binds. In addition, it definitely makes multiple contacts with the PTAP peptide. It binds two proline residues in particular in the PEPTAPPEE peptide: the first and third prolines, i.e., (P)E(P)TAPPEE. Rationale: For enhancement of binding affinity, attach the compound to a peptide via one of the aromatic rings of the compound.
- Omeprazole The binding mode is the same as in ATPase (via sulfonamide intermediate).
- the sulfenamide is made more quickly in acidic conditions and with heat. It is very reactive and can go on to form a dimer. Isolation of the dimer and testing indicates that it doesn't bind to TSG101.
- the sulfenamide has no antiviral activity in tissue culture ( FIG. 5 B ) most likely its charge prevents it from passing through cell membrane).
- Esomeprazole is more soluble than tenatoprazole. They exhibited comparable binding in the in vitro binding assay but Esomeprazole is less effective than Tenatoprazole in the tissue culture budding assay ( FIGS. 9 A- 9 C ).
- Pantoprazole, Lansoprazole/Dexlansoprazole (dexlansoprazole is the active enantiomer of the racemic lansoprazole), and Rabeprazole were in the NWU screen but were not considered hits.
- Esomeprazole is unstable in water: a red compound (presumably the rearranged dimer) is formed after only one hour at room temperature in water.
- Esomeprazole is insoluble in water, DMSO is fine. It is also more stable in DMSO, as long as it is not exposed to air/moisture/heat.
- Esomeprazole reacts slowly (presumably because a covalent bond is forming and the molecule must rearrange before binding). It seems to bind faster at higher temperature and lower pH. Reactions have been done at pH 5.8 as the recombinant TSG101 protein seems to be unstable at any pH above 7.5. In cytosolic conditions, pH is likely to be around 7.4, which might change the reactivity.
- Esomeprazole must rearrange to bind TSG101.
- the intermediate is short-lived and charged, possibly preventing it from crossing membranes. It should be noted that the number of moles of pro-drug is not the same as the number of moles that rearrange and bind to TSG101. Antiviral property might require higher prodrug concentration.
- Rabeprazole is the fastest binder; it converts to the sulfenamide faster than Omcprazole, Lansoprazole, and Pantoprazole versus Pantoprazole, which takes ⁇ 9 hr to form sulfenamide (Primi et al 1999;). Lanzoprazole is ⁇ 2 ⁇ as slow as Rabeprazole. Pantoprazole also perturbs residues AWAY from PTAP versus Tenatoprazole [In Primi et al, when half-lives of lansoprazole and rabeprazole were compared at pH 5.1, the lansoprazole half-life was 1.5 h while that of rabeprazole was 0.12 h]
- sulfenamide formation Dissolve each compound in water/buffer and measure the formation of colored compounds by UV-visible absorption, since the initial compound is colorless and the final compound (the sulfenamide dimer) is colored. Interestingly, they are all different colors. F15 and N16 are red, pantoprazole is yellow, rabeprazole is green and lansoprazole is purple.
- Panto- and Lanzo show two peaks: the first appears at the beginning of the experiment, usually within an hour or two, the second after ⁇ 3-4 hours (which seems to increase while the first drops).
- the compound may first bind to one cysteine (C73) and then to another (C87) or the binding may be biphasic.
- Tenato-, Rabe- and Esomeprazole show no evidence of two binding sites in the NMR.
- the compounds of the present invention include all hydrates, solvates, and complexes of the compounds used by this invention. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein.
- Compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
- the compounds described in the present invention are in racemic form or as individual enantiomers.
- the compounds of the subject invention may have spontaneous tautomeric forms.
- compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
- hydrogen atoms are not shown for carbon atoms having less than four bonds to non-hydrogen atoms. However, it is understood that enough hydrogen atoms exist on said carbon atoms to satisfy the octet rule.
- This invention also provides isotopic variants of the compounds disclosed herein, including wherein the isotopic atom is 2 H and/or wherein the isotopic atom 13 C. Accordingly, in the compounds provided herein hydrogen can be enriched in the deuterium isotope. It is to be understood that the invention encompasses all such isotopic forms.
- each stereogenic carbon may be of the R or S configuration.
- isomers arising from such asymmetry e.g., all enantiomers and diastereomers
- Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis, such as those described in “Enantiomers, Racemates and Resolutions” by J. Jacques, A. Collet and S. Wilen, Pub. John Wiley & Sons, N Y, 1981.
- the resolution may be carried out by preparative chromatography on a chiral column.
- the subject invention is also intended to include all isotopes of atoms occurring on the compounds disclosed herein.
- Isotopes include those atoms having the same atomic number but different mass numbers.
- isotopes of hydrogen include tritium and deuterium.
- isotopes of carbon include C-13 and C-14.
- any notation of a carbon in structures throughout this application when used without further notation, are intended to represent all isotopes of carbon, such as 12 C, 13 C, or 14 C.
- any compounds containing 13 C or 14 C may specifically have the structure of any of the compounds disclosed herein.
- any notation of a hydrogen in structures throughout this application when used without further notation, are intended to represent all isotopes of hydrogen, such as 1 H, 2 H, or 3 H.
- any compounds containing 2 H or 3 H may specifically have the structure of any of the compounds disclosed herein.
- Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art using appropriate isotopically-labeled reagents in place of the non-labeled reagents employed.
- the compounds used in the method of the present invention may be prepared by techniques well known in organic synthesis and familiar to a practitioner ordinarily skilled in the art. However, these may not be the only means by which to synthesize or obtain the desired compounds.
- the compounds used in the method of the present invention may be prepared by techniques described in Vogel's Textbook of Practical Organic Chemistry, A. I. Vogel, A. R. Tatchell, B. S. Furnis, A. J. Hannaford, P. W. G. Smith, (Prentice Hall) 5 th Edition (1996), March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Michael B. Smith, Jerry March, (Wiley-Interscience) 5 th Edition (2007), and references therein, which are incorporated by reference herein. However, these may not be the only means by which to synthesize or obtain the desired compounds.
- “effective” as in an amount effective to achieve an end means the quantity of a component that is sufficient to yield an indicated therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this disclosure.
- the specific effective amount will vary with such factors as the particular condition being treated, the physical condition of the patient, the type of mammal being treated, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed and the structure of the compounds or its derivatives.
- Periodic administration means repeated/recurrent administration separated by a period of time.
- the period of time between administrations is preferably consistent from time to time.
- Periodic administration can include administration, e.g., once daily, twice daily, three times daily, four times daily, weekly, twice weekly, three times weekly, four times weekly and so on, etc.
- to “treat” or “treating” encompasses, e.g., inducing inhibition, regression, or stasis of the disorder and/or disease.
- “inhibition” of disease progression or disease complication in a subject means preventing or reducing the disease progression and/or disease complication in the subject.
- any range disclosed herein it is meant that all hundredth, tenth and integer unit amounts within the range are specifically disclosed as part of the invention.
- 10 mg to 60 mg means that 10.01, 10.02 . . . 10.09; 10.1, 10.2 . . . 10.9; and 11, 12 . . . 59 mg unit amounts are included as embodiments of this invention.
- time disclosed herein i.e. weeks, months, or years
- 3-6 months means that 3 months and 1 day, 3 months and 1 week, and 4 months are included as embodiments of the invention.
- Another aspect of the invention comprises a compound used in the method of the present invention as a pharmaceutical composition.
- a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable carrier.
- the term “pharmaceutically active agent” means any substance or compound suitable for administration to a subject and furnishes biological activity or other direct effect in the treatment, cure, mitigation, diagnosis, or prevention of disease, or affects the structure or any function of the subject.
- Pharmaceutically active agents include, but are not limited to, substances and compounds described in the Physicians' Desk Reference (PDR Network, LLC; 64th edition; Nov. 15, 2009) and “Approved Drug Products with Therapeutic Equivalence Evaluations” (U.S. Department Of Health And Human Services, 30 th edition, 2010), which are hereby incorporated by reference.
- compositions which have pendant carboxylic acid groups may be modified in accordance with the present invention using standard esterification reactions and methods readily available and known to those having ordinary skill in the art of chemical synthesis. Where a pharmaceutically active agent does not possess a carboxylic acid group, the ordinarily skilled artisan will be able to design and incorporate a carboxylic acid group into the pharmaceutically active agent where esterification may subsequently be carried out so long as the modification does not interfere with the pharmaceutically active agent's biological activity or effect.
- the compounds used in the method of the present invention may be in a salt form.
- a “salt” is a salt of the instant compounds which has been modified by making acid or base salts of the compounds.
- the salt is pharmaceutically acceptable.
- pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols.
- the salts can be made using an organic or inorganic acid.
- Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like.
- Phenolate salts are the alkaline earth metal salts, sodium, potassium or lithium.
- pharmaceutically acceptable salt in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention.
- salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed.
- Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19).
- the compounds of the present invention may also form salts with basic amino acids such a lysine, arginine, etc. and with basic sugars such as N-methylglucamine, 2-amino-2-deoxyglucose, etc. and any other physiologically non-toxic basic substance.
- administering an agent may be performed using any of the various methods or delivery systems well known to those skilled in the art.
- the administering can be performed, for example, orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, intrathecally, into a cerebral ventricle, intraventicularly, intratumorally, into cerebral parenchyma or intraparenchchymally.
- the compounds used in the method of the present invention may be administered in various forms, including those detailed herein.
- the treatment with the compound may be a component of a combination therapy or an adjunct therapy, i.e. the subject or patient in need of the drug is treated or given another drug for the disease in conjunction with one or more of the instant compounds.
- This combination therapy can be sequential therapy where the patient is treated first with one drug and then the other or the two drugs are given simultaneously.
- These can be administered independently by the same route or by two or more different routes of administration depending on the dosage forms employed.
- a “pharmaceutically acceptable carrier” is a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the animal or human.
- the carrier may be liquid or solid and is selected with the planned manner of administration in mind.
- Liposomes are also a pharmaceutically acceptable carrier as are slow-release vehicles.
- the dosage of the compounds administered in treatment will vary depending upon factors such as the pharmacodynamic characteristics of a specific chemotherapeutic agent and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment with; and the desired therapeutic effect.
- a dosage unit of the compounds used in the method of the present invention may comprise a single compound or mixtures thereof with additional antitumor agents.
- the compounds can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
- the compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by injection, topical application, or other methods, into or topically onto a site of disease or lesion, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.
- the compounds used in the method of the present invention can be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or in carriers such as the novel programmable sustained-release multi-compartmental nanospheres (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
- a pharmaceutically acceptable carrier suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
- the unit will be in a form suitable for oral, nasal, rectal, topical, intravenous or direct injection or parenteral administration.
- the compounds can be administered alone or mixed with a pharmaceutically acceptable carrier.
- This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used.
- the active agent can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form.
- suitable solid carriers include lactose, sucrose, gelatin and agar.
- Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
- liquid dosage forms examples include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
- Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.
- Oral dosage forms optionally contain flavorants and coloring agents.
- Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.
- Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
- the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.
- Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
- Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
- Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
- the compounds used in the method of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
- Liposomes can be formed from a variety of phospholipids such as lecithin, sphingomyelin, proteolipids, protein-encapsulated vesicles or from cholesterol, stearylamine, or phosphatidylcholines.
- the compounds may be administered as components of tissue-targeted emulsions.
- the compounds used in the method of the present invention may also be coupled to soluble polymers as targetable drug carriers or as a prodrug.
- soluble polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamide-phenol, polyhydroxyethylasparta-midephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
- the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
- a class of biodegradable polymers useful in achieving controlled release of a drug
- a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
- Gelatin capsules may contain the active ingredient compounds and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
- powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration
- liquid dosage form For oral administration in liquid dosage form, the oral drug components are combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
- suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
- Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.
- Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
- water a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
- Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
- Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
- citric acid and its salts and sodium EDTA are also used.
- parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
- preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
- Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.
- the compounds used in the method of the present invention may also be administered in intranasal form via use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
- the dosage administration will generally be continuous rather than intermittent throughout the dosage regimen.
- Parenteral and intravenous forms may also include minerals and other materials such as solutol and/or ethanol to make them compatible with the type of injection or delivery system chosen.
- the compounds and compositions of the present invention can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
- the compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by topical administration, injection or other methods, to the afflicted area, such as a wound, including ulcers of the skin, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.
- the active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, powders, and chewing gum; or in liquid dosage forms, such as elixirs, syrups, and suspensions, including, but not limited to, mouthwash and toothpaste. It can also be administered parentally, in sterile liquid dosage forms.
- Solid dosage forms such as capsules and tablets, may be enteric-coated to prevent release of the active ingredient compounds before they reach the small intestine.
- Materials that may be used as enteric coatings include, but are not limited to, sugars, fatty acids, proteinaceous substances such as gelatin, waxes, shellac, cellulose acetate phthalate (CAP), methyl acrylate-methacrylic acid copolymers, cellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), and methyl methacrylate-methacrylic acid copolymers.
- CAP cellulose acetate phthalate
- PVAP polyvinyl acetate phthalate
- the compounds and compositions of the invention can be coated onto stents for temporary or permanent implantation into the cardiovascular system of a subject.
- the human immunodeficiency virus type-1 (HIV-1) is dependent on the cellular protein, Tsg101, for budding.
- Tsg101 The recruitment and delivery of Tsg101 to viral assembly sites is accomplished through its interaction with the virally-encoded structural precursor polyprotein, Gag, which directs viral particle release and has a Pro-Thr-Ala-Pro (PTAP) motif in its C-terminal p6 region that serves as docking site for Tsg101 (Garrus, J. E. et al. (2001); Martin-Serrano, J., et al. (2001); VerPlank, L. et al. (2001)).
- PTAP Pro-Thr-Ala-Pro
- Tsg101 The critical dependence on Tsg101 for productive viral replication is reflected in the fact that, despite motif duplication and extensive genetic heterogeneity in the HIV genome sequence, HIV variants with mutations within the PTAP motif have not been identified to date (Martins, A. N. et al. (2016)).
- the Tsg101 protein is a component of ESCRT-I, one of four complexes (ESCRT-0, -I, -II, -III) that comprise the highly conserved ESCRT (endosomal sorting complex required for transport) machinery.
- ESCRT-0, -I, -II, -III the highly conserved ESCRT (endosomal sorting complex required for transport) machinery.
- ESCRT-0, -I, -II, -III the highly conserved ESCRT (endosomal sorting complex required for transport) machinery.
- ESCRT-0, -I, -II, -III the highly conserved ESCRT (endo
- Gag and the recruited Tsg101 most likely meet in the cytosol and the complex brought to sites of assembly on the plasma membrane by virtue of membrane-binding determinants in the matrix domain of Gag (Ehrlich, L. S. & Carter, C. A. (2012); Dordor, A., et al. (2011)).
- UEV proteins Central to Tsg101 participation in Gag assembly is its ubiquitin E2 variant (UEV) domain.
- E3 enzymes ubiquitin E2 variant
- UEV proteins are highly conserved in evolution and constitute a family of proteins structurally related to, but distinct from, E2 enzymes.
- the Tsg101 UEV domain contains, in addition to an Ub-binding pocket, another pocket with affinity for PT/SAP motifs (Pornillos, O., Nat Struct Biol 9, 812-817, doi:10.1038/nsb856 (2002); Pornillos, O. et al. EMBO J 21, 2397-2406, doi:10.1093/emboj/21.10.2397 (2002); Teo, H., et al. (2004); Sundquist, W. I. et al. (2004)).
- the inventors hypothesized that Tsg101 uses its UEV domain to regulate protein levels of other proteins (VerPlank, L. et al. (2001)).
- Tsg101 was recruited as a chaperone to block non-productive Gag ubiquitination that might lead to its degradation, an idea supported by the fact that cyclin-specific E2 enzymes with Ser substituted for the active Cys are, in fact, dominant-negative inhibitors of cyclin destruction (Townsley, F. M., et al. (1997)). Mak, Cohen and collaborators demonstrated that, in concert with the E3 ligase MDM2, Tsg101 regulates protein levels of the transcription factor p53 (Li, L., et al. (2001); Ruland, J. et al. (2001)).
- Tsg101 provides chaperone function to HIV-1 Gag that is independent of its interaction with the PTAP motif, supporting the hypothesis that the domain provides a function in addition to its well-established role in ESCRT factor recruitment.
- Key tools in these studies are agents identified by high-throughput screening of a small molecule library for compounds capable of binding the Tsg101 UEV domain.
- the inhibitory effects of these probes on HIV-1 Gag assembly which were found to be highly specific, suggest that the agents can serve as leads for identification of potent inhibitors of HIV and other pathogens that require Tsg101 participation in viral replication.
- F15 esomeprazole
- N16 tenatoprazole
- F15 trade name Nexium
- the compounds share the same heteroaromatic core structure, differing in only one atom, and behaved very similarly in all experiments.
- pNL4-3 ⁇ Env, pIIIB-Env3-1, pCMV-Gag-HA encoding HIV-1 Gag C-terminally tagged with hemagglutinin, as previously described in the art were used (Watanabe et al. (2013)).
- pCMV-Gag-EGFP encoding HIV-1 Gag C-terminally tagged with green fluorescent protein (GFP)
- pLLEXP1-hTsg101-myc encoding full-length human Tsg101 C-terminally tagged with myc as previously described in the art were used (Goff, A., et al. (2003)).
- pLLEXP1-hTsg101-myc and pLLEXP1-hTSG101-FLAG were used as templates for site-directed mutagenesis to generate single amino acid substitution mutants: C73A and C87A (Lu, Q., et al. (2003)).
- Primary antibodies were: Rb anti-CA; mouse anti-HA and anti-actin (Biolegend); mouse anti-myc (Santa Cruz Biotechnology). Secondary antibodies were: goat anti-mouse IgG Alexa Fluor 680 and Texas Red tagged anti-mouse IgG (Molecular Probes); goat anti-rabbit IRDye800 (Rockland).
- VLP virus-like particles
- pCMV-Gag-HA virus-like particles
- media-associated p24 was determined by ELISA (Immunodiagnostics, Inc.) and equivalent amounts of p24 were used to infect HeLa-CD4+-LTR-3 gal cells for infectivity measurement by the multinuclear activation of a galactosidase indicator (MAGI) assay.
- MAGI galactosidase indicator
- VLP isolation and analysis media was filtered (0.45 micron), pelleted through a 20% sucrose cushion and examined by Western blotting.
- cell-associated Gag analysis cell pellets were lysed with either Triton X-100 or RIPA buffer with complete mini protease inhibitor cocktail (Roche) and analyzed by Western blotting. Protein bands were visualized using an infrared-based imaging system (Odyssey, LI-COR Biotechnology) and band intensities measured using the Li-Cor Odyssey software version 2.1.15. Virus particle release efficiency was calculated [VLP signal intensity/(VLP signal intensity+cell lysate signal intensity)]. Quantification analyses plot the data mean with error bars signifying plus or minus 1 standard deviation (SD).
- Hela cells grown on cover slips were transfected with pCMV-Gag-EGFP alone or together with pLLEXP1-hTsg101-myc.
- Cells were fixed in 4% formaldehyde (Sigma) and permeabilized in 0.1% Triton X-100.
- Tsg101 was detected in the samples by indirect immunofluorescence using anti-myc Mab and Texas Red anti-mouse IgG. Nuclei were stained with Hoechst.
- 293T cells grown on ACLAR film that have been transfected and treated as described were fixed in 2.5% EM grade glutaraldehyde in PBS, soaked in 2% osmium tetroxide, dehydrated in a graded series of ethyl alcohol solutions and embedded in Durpan resin. Thin sections of 80 nm were counterstained with uranyl acetate and lead citrate and viewed with a FEI Tecanal BioTwinG2 electron microscope.
- Tsg101 UEV domain (residues 2-145) was encoded in a pET-28b vector (Novagen—EMD Millipore), which included a TEV protease cleavage site (His 6 -TEV-Tsg101 2-145 ).
- Tsg101 protein was expressed in Rosetta 2 (DE3) pLysS E.
- coli competent cells EMD Millipore
- M9 medium containing 50 mgL ⁇ 1 kanamycin (Sigma) and 34 mgL ⁇ 1 chloramphenicol (Sigma), supplemented with 15 NH 4 Cl and either natural abundance glucose or [U- 13 C]-glucose to obtain 15N-Tsg101 UEV and 15 N/ 13 C-Tsg101 UEV, respectively.
- the proteins were purified to homogeneity using immobilized nickel ion affinity chromatography (HisTrap FF, GE Healthcare) before and after TEV protease cleavage to remove the N-terminal His 6 tag, followed by size-exclusion chromatography (HiLoad 16/60 Superdex 75 pg, GE Healthcare) for final purification. Cleavage by TEV protease resulted in a non-native glycine at the N-terminus (residue 1). NMR samples contained ⁇ 0.6 mM Tsg101 UEV, 20 mM potassium phosphate (pH 5.8), 50 mM NaCl, and 8% 2 H2O. For the 13 C-aromatic, 13 C-aliphatic, and 13 C-filtered NOESY experiments, the sample was exchanged into the same buffer dissolved in 99.96% D20 (Cambridge Isotope Laboratories).
- N16 (20 mM solution, DMSO) was added to Tsg101 UEV domain in a 10:1 ratio (N16 excess). Complete formation of the N16 UEV complex was observed at 2 hours by following chemical shift perturbations, which coincided with a red coloring of the solution. Since the complex was covalent, excess unbound N16 and DMSO could be removed by Amicon Ultra centrifugal filtration (MWCO 10 kDa, Millipore).
- LC-MS confirmed 99% 15 N-labeling (16727.8 Da for 15 N-Tsg101 UEV vs expected 16729.2 Da for 100% 15 N-labeling) and 98% 13 C-labeling (17471.5 Da for 15 N/ 13 C-Tsg101 UEV assuming 99% 15 N-labeling vs expected 17488.2 Da for 100% 15 N- and 13 C-labeling).
- Covalent attachment of N16 was also confirmed by LC-MS (17057.2 Da for N16 15 N-Tsg101 UEV vs expected 17057.2 Da, assuming loss of oxygen associated with rearrangement).
- Tsg101 UEV-N16, UEV-PTAP, UEV-Ub, UEV-N16-PTAP, and UEV-N16-Ub all in Tsg101 NMR buffer: 20 mM potassium phosphate, 50 mM NaCl, pH 5.8, with UEV concentration of 200 ⁇ M.
- PTAP (Ace-NFLQSRPEPTAPPEE-CONH2, Bio-Synthesis, Texas), is a synthetic peptide based on residues 15-16 of the HIV-1 Gag WT spacer peptide 2 ( 15 NF 16 ) and 1-13 of the HIV-1 Gag WT p6 sequence ( 1 LQSRPEPTAPPEE 13 ), which was dissolved in Tsg101 NMR buffer at a concentration of 1 mM before addition to Tsg101 UEV or UEV-N16 at a final 1:1 ratio.
- Ub wild-type, unlabeled ubiquitin, 936 ⁇ M was purified as previously described and was dialyzed against Tsg101 NMR buffer along with UEV or UEV-N16 prior to mixing at a final 1:1 ratio (Lazar, G. A., et al. (1997)).
- the assignment of Ub in complex with Tsg101 UEV and UEV-N16 was carried out using chemical shift titrations, by measuring HSQC spectra at a 1:0, 1:0.5, and 1:1 ratio of UEV or UEV-N16 to Ub.
- the assignment of the UEV-PTAP complex was carried out using a 15 N-edited NOESY spectrum and by comparison with the BMRB chemical shifts previously deposited for the structure of Tsg101 UEV in complex with a PTAP peptide (BMRB: 5532, PDB: 1M4Q, 1M4P) (Pornillos, O., et al. Nat Struct Biol 9:812-817, doi:10.1038/nsb856 (2002)).
- NMR data were acquired at 300 K on Bruker 600, 800, and 900 MHz spectrometers, each equipped with a cryogenic probe, using 13 C/ 15 N-Tsg101 in complex with natural abundance N16.
- Spectra were processed using NMRPipe and analyzed using CCPN Analysis 2.4.1 (Delaglio, F. et al. (1995); Vranken, W. F. et al. (2005)).
- the structure of the Tsg101 UEV domain in complex with N16 was calculated using Xplor-NIH (Schwieters, C. D., et al. (2003); Schwieters, C. D., et al. (2006)). Simulated annealing was used in combination with NOE distance restraints, dihedral angle restraints, and hydrogen bond restraints. Distance restraints were calculated from NOE peak heights using CCPN Analysis 2.4.1 (Vranken, W. F. et al. (2005)). Dihedral angle restraints were derived from backbone chemical shift data using TALOS N (Shen, Y. & Bax, A. (2013)).
- Hydrogen bond restraints were obtained by predicting secondary structure propensity using MICS and combining with known hydrogen bonds from the Tsg101 UEV domain structure in the free form (PDB: 1KPP) (Shen, Y. & Bax, A. (2012); Pornillos, O. et al. EMBO J 21:2397-2406, doi:10.1093/emboj/21.10.2397 (2002)). 200 structures were calculated using simulated annealing, of which the 20 with lowest energy were used for further refinement.
- FIG. 15 To investigate whether the ability to bind the UEV domain could affect Tsg101's function during HIV's budding process, viral particle production was tested ( FIG. 15 ).
- ELISA enzyme-linked immunosorbent assay
- N16 also reduced viral particle production in a spreading infection of Jurkat cells infected with NL4-3 ( FIG. 16 ). After 15 days, virus production was reduced by 15-fold. Cell viability was maintained under these conditions of sustained drug exposure as indicated by trypan blue viability assay every 3rd day. Subsequent incubation in media without inhibitor resulted in a 10-fold resurgence of the virus after 4 days. Following the re-addition of N16 to the media, virus titer at this point was reduced 50-fold 4 days indicating maintenance of drug susceptibility.
- Electron microscopy was used to identify the event arrested by N16 treatment.
- Four morphologically identifiable stages comprise HIV-1 viral particle assembly: Deposition of electron-dense material at the cell surface is followed by progressive membrane deformation that results in a protruding bud that is eventually released as an immature virus particle. This particle undergoes morphogenetic rearrangement into the mature infectious particle ( FIG. 15 C , top, designated as ‘Early’, ‘Tethered’, ‘Released Immature’, and ‘Released Mature’, respectively).
- the untreated virus exhibited all of these stages to various degrees.
- N16 significantly aggravated the transition from ‘Early’ to ‘Tethered’, thereby impairing production of the mature particle.
- Gag contains all determinants necessary for formation and budding of immature virus-like particles (VLPs) (Ehrlich, L. S. & Carter, C. A. (2012); Dordor, A., et al. (2011)).
- VLPs immature virus-like particles
- N16 treatment was accompanied by dose-dependent reduction in both the steady-state level of Gag intracellular accumulation and the amount of VLP formation.
- N16 also inhibited VLP release from HeLa cells, Gag intracellular accumulation was not affected ( FIG. 17 A ).
- FIG. 17 A As shown in FIG.
- proteases aprotinin, 2 ⁇ g/ml; pepstatin, 1 ⁇ g/ml; leupeptin, 2.5 ⁇ g/ml; TPCK, 90 ⁇ M; and PMSF, 35 ⁇ g/ml was also effective.
- Tsg101 localization to the midbody of dividing cells requires its recruitment to that location by centrosomal protein of 55k (CEP55) which binds a site in the Tsg101 Pro-rich domain (aa 154-166) (Lee, H. H., et al. (2008)). Finding this function unaffected at a concentration inhibitory to virus budding is consistent with the lack of any indication that cell division was reduced in the presence of N16.
- Vps23 the orthologue of Tsg101 in yeast
- Doa4 a deubiquitinating enzyme
- FIG. 21 A shows that fusion of the catalytic domain of the Herpes Simplex virus UL36 deubiquitinating enzyme (DUb) onto Gag inhibited budding, as expected based on previous studies (Sette et al.). Quantitative analysis indicated that VLP release efficiency was reduced ⁇ 50-fold ( FIG. 21 A, bottom panel).
- FIG. 21 B shows the effect of N16. As expected based on the results above, budding directed by WT Gag was inhibited by 50 ⁇ M N16 ( FIG. 21 B , top, left).
- the high-resolution structure of the N16-Tsg101 UEV complex was solved using NMR, and the atomic interactions between N16 and Tsg101 were probed (PDB ID 5VKG, BMRB ID 30285, FIG. 14 ).
- the N16 binding site of Tsg101 comprised a region surrounding residue C73 that included D40, S41, Y42, N54, T56, W75 and K90 ( FIGS. 22 A and 22 B ), which correlated well with the observed chemical shift perturbations of N16 with Tsg101 ( FIGS. 22 C and 22 D, 23 ).
- Tsg101 chemical shift perturbations caused by PTAP binding showed the same general profile with and without pre-incubation of N16, with some differences around residues 87-98 ( FIGS. 22 E and 22 F, 24 ). This contrasts with the Ub-binding pocket perturbation profile, which indicated N16 interfered throughout the pocket resulting in a significantly lower Tsg101-Ub binding affinity in the presence of N16 ( FIGS. 22 G and 22 H, 25 ).
- N16 ( FIG. 26 A , i) is a prodrug that is acid-activated into derivatives ( FIG. 26 A , ii and iii) that form disulfide linkages (e.g., FIG. 26 A , iv) (Shin, J. M. & Kim, N. (2013)).
- the prodrug but not the charged sulfenamide derivative, can cross the plasma membrane barrier.
- Cys73 the Cys residue in the Tsg101 UEV domain that was perturbed by N16, formed a disulfide linkage with a derivative produced inside the cell following N16 uptake.
- Mass spectrometry was performed to examine for covalent bond formation following mixing of drug and the Tsg101 UEV domain.
- the substitution of Ala for C73, but not C87, is predicted to permit Gag-Tsg101 co-localization in the presence of the drug by preventing the covalent blockade.
- N16 failed to prevent co-localization of Gag and Tsg101 C73A -myc.
- N16 effectively eliminated co-localization of Gag and Tsg101 C87A -myc.
- Tsg101 residue C73 is the target of N16, then knocking down endogenous Tsg101 and providing a siRNA-resistant version of the C73A mutant should render HIV-1 assembly/release insensitive to N16.
- Tsg101 in HIV-1 production is as conduit to the membrane-remodeling machinery associated with ESCRT-III, which is required for virus budding (Hurley, J. H. & Hanson, P. I. (2010); Adell, M. A. & Teis, D. (2011); Votteler, J. & Sundquist, W. 1. (2013)).
- the Tsg101-Gag PTAP binding activity is mainly responsible for the virus' ability to recruit Tsg101 to Gag assembly sites on the plasma membrane. Determinants within Gag direct the complex to budding sites on the plasma membrane where the Tsg101-mediated recruitment of ESCRT-III membrane scission machinery facilitates virus particle release from the cell.
- Gag ubiquitination permits engagement of the Tsg101 Ub-binding pocket, which for WT Gag serves to significantly increase Gag-Tsg101 binding affinity (Pornillos et al., EMBO J 21, 2397-2406, (2002)) and for P7L, provides a way of recruiting Tsg101.
- the compounds can be expected to prevent such release.
- MG132 is a structurally & functionally unrelated proteasome inhibitor which reversibly blocks all activities of the 26S proteasome but is not as specific as bortezomib (Goldberg (2012)). MG132 is known to have off-target effects, e.g., it inhibits calpain and clasto-Lactacystin ⁇ -lactone which inhibits cathepsin A. Although Schwartz et al.
- MG132 treatment results in ultrastructural changes in budding virions similar to those resulting from mutations in the PTAP Late assembly domain (Schubert, U. et al. (2000)), while the impact of N16 appears to be at an earlier stage.
- N16 NEM contribution to be defined
- Gag-destabilizing effect of N16 observed in 293T but not HeLa cells is an “off-target” effect of N16 in 293T cells or is in some way linked to an indirect impact on Tsg101 function in those cells.
- This application proposes a Tsg101 chaperone function that is based on the participation of the Ub binding pocket in temporal and/or spatial balancing of Gag ubiquitination and deubiquitination during budding.
- Tsg101 makes a previously unappreciated contribution to virus budding that appears to be required early in the budding process and distinct from the recruitment of ESCRT-III that is critical to HIV egress. Moreover, this function is required whether or not the PTAP pocket in the Tsg101 protein is engaged, as evident from P7L susceptibility. Possibly, as the binding is covalent, the F15/N16-modified Tsg101 might exert a trans-dominant-negative interfering influence on a function required for Alix-mediated P7L budding and thereby affect egress even if direct binding does not normally occur. That both Tsg101-driven and Alix-driven budding was inhibited by an agent (N16) that disrupts Tsg101 Ub-binding activity implies a requirement for this Tsg101 chaperone function in a fundamental aspect of budding.
- Targeting of the Gag-Tsg101 interaction for inhibition of HIV budding has been an active field over the last fifteen years, mostly focusing on interference with PTAP binding (Tavassoli, A. et al. (2008); Chen, H., et al. (2010); Kim, S. E. et al. (2011); Lu, J. et al. (2014)).
- a synthetic peptide that mimics the PTAP motif could compete for the PTAP binding pocket of Tsg101 in cells.
- the wild-type synthetic peptide 5 PEPTAPPEE 13 displays a low binding affinity to Tsg101 in vitro, with a K d of 54 ⁇ M (Liu, F. et al.
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Abstract
Description
-
- a) obtaining a test compound;
- b) contacting the test compound with a cellular polypeptide, or fragment thereof, including a UEV domain Ub-binding pocket, in the presence of an ubiquitin-modified polypeptide of the virus, or fragment thereof, that is capable of binding said UEV domain Ub-binding pocket, or an ubiquitin-modified cellular polypeptide for the virus' production other than the cellular polypeptide that includes the UEV domain Ub-binding pocket, or fragment thereof, that is capable of binding said UEV domain Ub-binding pocket;
- c) determining whether the test compound inhibits or disrupts the formation of an associative complex comprising the cellular polypeptide, or fragment thereof, including a UEV domain Ub-binding pocket and the ubiquitin-modified polypeptide of the virus, or fragment thereof, that is capable of binding said UEV domain Ub-binding pocket, or the ubiquitin-modified cellular polypeptide for the virus' production other than the cellular polypeptide that includes the UEV domain Ub-binding pocket, or fragment thereof, that is capable of binding said UEV domain Ub-binding pocket, thereby identifying the test compound as a compound that binds a UEV domain Ub-binding pocket of a cellular polypeptide with an affinity sufficient to inhibit or disrupt formation of an associative complex in a cell.
-
- a) an ubiquitin-modified polypeptide of the virus, or fragment thereof, that is capable of binding said UEV domain Ub-binding pocket; or
- b) an ubiquitin-modified cellular polypeptide for the virus' production other than the cellular polypeptide that includes the UEV domain Ub-binding pocket, or fragment thereof, that is capable of binding said UEV domain Ub-binding pocket.
-
- wherein:
- R1 is H, halogen, C1-6 alkyl unsubstituted or substituted with halogen, C1-8 alkoxy unsubstituted or substituted with fluorine or a cycloalkyl group of 3-6 carbon atoms, chlorodifluoromethoxy, fluoroalkyloxy, C1-6 alkoxycarbonyl or carboxyl group, or alkanoyl;
- R2 is H, halogen, C1-6 alkyl unsubstituted or substituted with halogen, C1-6 alkoxy unsubstituted or substituted with fluorine, C1-6 alkoxycarbonyl or carboxyl group, or alkanoyl;
- R3 is H, methyl or ethyl;
- R4 is H, C1-6 alkyl, C1-3 alkoxy, methoxyethoxy, or ethoxyethoxy;
- R5 is H, methyl, C1-5 alkoxy unsubstituted or substituted with fluorine, methoxyethoxy, ethoxyethoxy, or —OC2-10 alkyl-OC0-6 alkyl;
- R6 is H, C1-3 alkyl, C1-3 alkoxy, methoxyethoxy, or ethoxyethoxy;
- n is 0-2; and
- X is C, C—R1 or —R2, or N.
-
- wherein:
- R1 is halogen, C1-6 alkyl substituted with halogen, chlorodifluoromethoxy, or C3-6 alkoxycarbonyl or carboxyl group;
- R2 is halogen, C1-6 alkyl substituted with halogen, C1-6 alkoxy unsubstituted or substituted with fluorine, or C3-6 alkoxycarbonyl or carboxyl group;
- R3 is H;
- R4 is C2-6 alkyl or C3 alkoxy;
- R5 is C3-5 alkoxy unsubstituted, C2-5 alkoxy substituted with fluorine, or —OC2-10 alkyl-OC0-6 alkyl;
- R6 is C2-3 alkyl or C3 alkoxy;
- n is 0-2; and
- X is C, or C—R1 or —R2.
-
- R1 is C1-8 alkoxy unsubstituted or substituted with a cycloalkyl group of 3-6 carbon atoms or fluoroalkyloxy;
- R2 is H;
- R3 is H;
- R4 is H or methyl;
- R5 is H, methyl or methoxy;
- R6 is H or methyl;
- n is 1; and
- X is N.
-
- R1 and R2 are independently H, CJ-6 alkyl, halogen, methoxycarbonyl, ethoxycarbonyl, alkoxy, or alkanoyl;
- R3 is H, methyl, or ethyl;
- R4-R6 are independently H, methyl, methoxy, ethoxy, methoxyethoxy, or ethoxyethoxy, wherein R4-R6 are not all hydrogen, and wherein if two of R4-R6 are hydrogen, then the remaining group is not methyl;
- n is 1; and
- X is C, or C—R1 or —R2.
-
- R1 is C1-3 alkoxy substituted with fluorine, or chlorodifluoromethoxy;
- R2 is H, halogen, trifluoromethyl, C1-3 alkyl, or C1-3 alkoxy unsubstituted or substituted with fluorine;
- R3 is H;
- R4 and R6 are independently H, C1-3 alkyl, or C1-3 alkoxy, wherein R4 and R6 are not the same and wherein one of R4 and R6 is C1-3 alkoxy;
- R5 is C1-3 alkoxy;
- n is 0 or 1; and
- X is C, or C—R1 or —R2.
-
- R1 is H, methoxy, or trifluoromethyl;
- R2 is H;
- R3 is H;
- R4 and R6 are independently H or methyl;
- R5 is C2-5 alkoxy substituted with fluorine;
- n is 0 or 1; and
- X is C, or C—R1 or —R2.
-
- R1 and R2 are independently H, halogen, C1-6 alkyl unsubstituted or substituted with halogen, C1-6 alkoxy, or C1-6 alkoxycarbonyl or carboxyl group;
- R3 is H;
- R4 is C1-6 alkyl;
- R5 is —OC2-10 alkyl-OC0-6 alkyl;
- R6 is H;
- n is 0-2; and
- X is C, or C—R1 or —R2.
-
- or a pharmaceutically acceptable salt thereof.
-
- or a pharmaceutically acceptable salt thereof.
-
- a) obtaining a test compound;
- b) contacting the test compound with a cellular polypeptide, or fragment thereof, including a UEV domain Ub-binding pocket, in the presence of an ubiquitin-modified polypeptide of the virus, or fragment thereof, that is capable of binding said UEV domain Ub-binding pocket, or an ubiquitin-modified cellular polypeptide for the virus' production other than the cellular polypeptide that includes the UEV domain Ub-binding pocket, or fragment thereof, that is capable of binding said UEV domain Ub-binding pocket;
- c) determining whether the test compound inhibits or disrupts the formation of an associative complex comprising the cellular polypeptide, or fragment thereof, including a UEV domain Ub-binding pocket and the ubiquitin-modified polypeptide of the virus, or fragment thereof, that is capable of binding said UEV domain Ub-binding pocket, or the ubiquitin-modified cellular polypeptide for the virus' production other than the cellular polypeptide that includes the UEV domain Ub-binding pocket, or fragment thereof, that is capable of binding said UEV domain Ub-binding pocket, thereby identifying the test compound as a compound that binds a UEV domain Ub-binding pocket of a cellular polypeptide with an affinity sufficient to inhibit or disrupt formation of an associative complex in a cell.
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