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 employing both commercial and synthesized analogs (> 200 total) and identified the key structural elements necessary for activity (i.e., the essential pharmacophore). Iterative rounds of synthesis and testing in a robust panel of anti-HIV and toxicity assays, produced patentable new analogs that are 100-fold more potent than our original screening hits and with therapeutic indices >4000, exceeding our original goals. Having successfully completed key milestones towards submission of an Investigational New Drug (IND), potential corporate partners have requested that we perform virology experiments to fully characterize the activity of the molecules with a diverse panel of viral isolates and cell types, and in combination with currently approved drugs.
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 detailed virology studies to fully characterize the activity of the molecules with a diverse panel of viral isolates and cell types, and in combination with currently approved drugs.
Project Terms: Affect; Agreement; Aminoglycoside Antibiotics; analog; Antibiotics; Antiviral Agents; Azithromycin; base; Biological Assay; Biotechnology; Caring; Cell Line; Cell Nucleus; Cell Survival; cell type; Cells; Cessation of life; Clinical Drug Development; combat; Companions; Complex; Consensus; Cytoplasm; Development; drug discovery; Drug resistance; drug resistant virus; Drug Targeting; Elements; Enzyme-Linked Immunosorbent Assay; Face; Family; FDA approved; Funding; Genetic; Genetic Transcription; Goals; Grant; HIV; HIV therapy; in vivo; inhibitor/antagonist; Inhibitory Concentration 50; Integrase Inhibitors; Investigational Drugs; Investments; Laboratories; Lead; Linezolid; Macrolide Antibiotics; Marketing; Messenger RNA; Molecular; Monitor; novel; Nuclear Export; Oxazolidinones; Peptide Hydrolases; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacologic Substance; pharmacophore; Phase; Play; pre-clinical; programs; protein complex; public health relevance; Published Comment; Regimen; Request for Applications; research study; Resistance; response; RNA; RNA-Directed DNA Polymerase; RNA-Protein Interaction; Role; scaffold; Scientist; screening; Small Business Innovation Research Grant; Small Business Technology Transfer Research; small molecule; Staging; Stress; Structure; System; Testing; Therapeutic; Therapeutic Index; thienopyridine; Toxic effect; Translating; Translations; Viral; Viral Antigens; viral resistance; virology; Virus; Virus Diseases; Work
