There is a significant need for novel HIV therapies given the emergence of viruses resistant to existing drug regimens. The Rev-RRE protein-RNA interaction in HIV plays an essential role in the transport of viral mRNA from the nucleus to the cytoplasm where it can be translated or packaged. Previously we identified the thienopyridine scaffold that inhibited HIV replication and by targeting HIV Rev. We carried out extensive structure-activity (SAR) studies producing patentable new analogs that are 100-fold more potent than our original screening hits and with therapeutic indices >10,000, exceeding our original goals. Having successfully completed key milestones towards submission of an Investigational New Drug (IND), we propose to carry out a detailed study of the mechanism of action of the inhibitors. This study is a key scientific milestone that will open many corporate and venture opportunities, as well as significantly strengthen our opportunity to access SBIR/STTR Phase II funding. The work described in this proposal has a high likelihood for success given that in preliminary studies we have shown that a mutant in the RRE confers resistance to the compound.
Public Health Relevance Statement: Public Health Relevance: We previously carried out a structure-activity study of a promising Rev inhibitor and identified the key structural elements necessary for activity. We propose to carry out experiments to establish the molecular mechanism of the molecule.
Project Terms: analog; Antiviral Agents; base; Biochemical; Biological Assay; Cell Nucleus; Cells; Consensus; Cytoplasm; design; drug discovery; Drug resistance; drug resistant virus; Elements; Enzyme-Linked Immunosorbent Assay; Evaluation; Family; Fluorescent in Situ Hybridization; Funding; Generations; Genetic; Goals; Government; Grant; HIV; HIV therapy; HIV-1; Individual; Infection; inhibitor/antagonist; Investigational Drugs; Kinetics; Lead; Measures; Messenger RNA; Methods; Molecular; Monitor; mutant; Mutation; next generation; novel; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Play; Population; pressure; programs; protein complex; Proteins; public health relevance; Published Comment; Regimen; Reporter; research study; Resistance; resistance mutation; RNA; RNA Splicing; RNA Transport; RNA-Protein Interaction; Role; scaffold; Scientist; screening; Small Business Innovation Research Grant; Small Business Technology Transfer Research; small molecule; Structure; success; System; Testing; Therapeutic Index; thienopyridine; Toxic effect; Translating; United States National Institutes of Health; Viral; Virus; Virus Inhibitors; Work
