Methods of inhibiting viruses using compositions targeting TSG101-ubiquitin interaction
Inventors
Carter, Carol • Erlich, Lorna • Tjandra, Nico • Davison, Madeleine
Assignees
Research Foundation of the State University of New York • US Department of Health and Human Services
Publication Number
US-12059413-B2
Publication Date
2024-08-13
Expiration Date
2037-10-30
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Abstract
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.
Core Innovation
The invention provides a method of inhibiting virus release from a cell by contacting the cell with a compound that binds to the ubiquitin E2 variant (UEV) domain of a cellular polypeptide, specifically Tsg101 or a fragment thereof, with an affinity sufficient to inhibit or disrupt the binding of Tsg101 to ubiquitin. This inhibition disrupts formation of associative complexes involving ubiquitin-modified viral or cellular polypeptides critical for virus production.
The invention addresses the challenge posed by enveloped viruses, such as HIV-1, that engage cellular machinery involved in protein internalization but must evade it to facilitate viral egress. The virus employs measures to prevent its proteins from undergoing normal internalization pathways which would hinder virus release. The proposed method targets the interaction between Tsg101 and ubiquitin, a key step exploited by viruses, to inhibit viral particle budding and release.
The approach exploits the UEV domain's role in binding ubiquitin on viral or cellular proteins necessary for viral assembly and release. Compounds selectively bind the UEV domain, specifically modifying residues such as Cys73, to inhibit ubiquitin binding and thus disrupt viral release. This targeted interference affects an early stage of viral budding, distinct from the PTAP motif binding, providing a novel means to inhibit viral replication by perturbing Tsg101-ubiquitin interactions.
Claims Coverage
The patent contains multiple independent claims covering methods of inhibiting viral release and treating viral infections using compounds targeting the UEV domain of Tsg101, specifying their binding affinities and chemical structures.
Method of inhibiting viral release by disrupting Tsg101-ubiquitin binding
A method comprising contacting a cell with a compound that binds the ubiquitin E2 variant (UEV) domain of Tsg101 or fragment thereof, with an affinity sufficient to inhibit or disrupt at least 50% of the binding of Tsg101 to ubiquitin, thereby inhibiting release of viruses including HIV-1 and other listed viruses.
Inhibition of associative complex formation involving UEV domain and ubiquitin-modified polypeptides
A method where the compound binds the UEV domain with affinity sufficient to inhibit or disrupt formation of an associative complex comprising the UEV domain-containing polypeptide and either ubiquitin-modified viral polypeptides or ubiquitin-modified cellular polypeptides involved in virus production.
Treatment of viral infection by administration of UEV domain-binding compounds
A method of treating patients infected with viruses by administering a compound that binds the UEV domain Ub-binding pocket of Tsg101 protein in an amount effective to inhibit its binding to ubiquitin, thereby treating infections by a wide range of viruses including HIV-1, Hepatitis C, Influenza, and others.
Chemical structure of compounds binding the UEV domain
Specific compound structures described, including substituted heteroaromatic compounds with defined substituent groups (R1-R6, n, X) that covalently bind Tsg101 UEV domain, notably binding at Cys73 and inhibiting ubiquitin interaction.
Applicability to human and plant cells
The method applies to cells of human or plant origin, including inhibiting release of plant viruses such as Tomato Bushy Stunt virus and Brome mosaic virus.
The claims define methods for inhibiting viral release and treating viral infections by targeting and disrupting ubiquitin binding to the ubiquitin E2 variant domain of Tsg101 using specific compounds. These methods cover associative complex inhibition involving viral and cellular ubiquitinated proteins and specify chemical structures of effective compounds. The claims further extend the application to multiple viruses and cell types, underscoring the broad inventive scope targeting the Tsg101-ubiquitin interaction.
Stated Advantages
Minimizes emergence of drug resistance by targeting a highly conserved cellular protein rather than viral proteins.
Enables delivery as long-acting and sustained-release formulations to improve patient adherence.
Uses compounds already demonstrated to be safe, well-tolerated, and market acceptable for other indications.
Provides high specificity for virus-required targets, minimizing impact on host cell functions.
Offers broad spectrum antiviral efficacy as many pathogens require Tsg101 for trafficking.
Efficacy does not require direct binding of viral-encoded proteins to Tsg101.
Therapeutics can be presented as pro-drugs requiring local activation, reducing off-target effects.
Documented Applications
Inhibiting release of viruses including Human Immunodeficiency virus type 1 (HIV-1), Hepatitis C virus, Human Papillomavirus, Herpes Simplex virus type 1, Dengue virus, Japanese Encephalitis virus, Human Parainfluenzavirus Type 1, Epstein Barr Virus, Mopeia virus, Tacaribe virus, Human Cytomegalovirus, Measles virus and Influenza virus from human cells.
Treatment of patients infected with the above viruses by administering compounds targeting the Tsg101 UEV domain to inhibit viral release.
Inhibition of plant viruses such as Tomato Bushy Stunt virus and Brome mosaic virus from plant cells.
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