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. In preliminary work, two distinct assays targeting the HIV Rev protein identified structurally similar hits possessing a thienopyridine scaffold. Compounds of this class were subsequently shown to inhibit HIV replication and to exhibit low toxicity. An expanded study of the thienopyridine class using purchased analogs revealed clear structure-activity relationships (SAR), suggesting a well-defined molecular target and the potential for further improvement in potency through chemical optimization. Here, we propose to conduct a systematic structure-activity study of the thienopyridine family using synthesized analogs and employing a robust panel of antiviral, reporter, and ADME-Tox assays. The initial study of thienopyridines with purchased analogs provided useful information concerning pyridine ring SAR. However, a comprehensive evaluation of these compounds and the identification of the essential pharmacophore imbedded within them will require chemical synthesis. Thus, we plan to perform multiple rounds of analog synthesis and screening, allowing emerging SAR to guide further optimization. The successful conclusion of these studies will see the identification of one or more lead chemotypes, thus enabling lead optimization studies in a subsequent phase of work.
Public Health Relevance: A proposed structure-activity study of a promising Rev inhibitor is described. New analogs will be synthesized or procured from vendors and then tested for antiviral activity and drug-like properties.
Public Health Relevance Statement: Narrative A proposed structure-activity study of a promising Rev inhibitor is described. New analogs will be synthesized or procured from vendors and then tested for antiviral activity and drug-like properties.
Project Terms: AIDS Virus; Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; Aminoglycoside Agents; Aminoglycoside Antibiotics; Aminoglycoside Drugs; Antibiotic Agents; Antibiotic Drugs; Antibiotics; Antibiotics, Aminoglycoside; Antiviral Agents; Antiviral Drugs; Antivirals; Assay; Azadose; Azithromycin; Azitrocin; Azythromycin; Bayer Brand of Azithromycin Dihydrate; Bioassay; Biologic Assays; Biological Assay; Cell Line; Cell Lines, Strains; Cell Nucleus; Cell Survival; Cell Viability; CellLine; Cells; Chemicals; Classification; Clinical; Complex; Cytoplasm; Drug Delivery; Drug Delivery Systems; Drug Evaluation, Preclinical; Drug Screening; Drug Targeting; Drug Targetings; Drugs; Elements; Evaluation; Evaluation Studies, Drug, Pre-Clinical; Evaluation Studies, Drug, Preclinical; Exhibits; Family; Gene Products, RNA; Gene Transcription; Genetic; Genetic Transcription; Government; Grant; HIV; HIV therapy; HIV-1; HIV-I; HIV1; HTLV-III; Hand; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; Human immunodeficiency virus 1; Immunodeficiency Virus Type 1, Human; In Vitro; Kinetic; Kinetics; LAV-HTLV-III; Lead; Linezolid; Lymphadenopathy-Associated Virus; Mack Brand of Azithromycin Dihydrate; Macrolide Antibiotics; Marketing; Measures; Medication; Messenger RNA; Miscellaneous Antibiotic; Modeling; Molecular; Molecular Target; N-((3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl)methyl)acetamide; Nuclear Export; Nucleus; Oxazolidinones; Pb element; Persons; Pfizer Brand of Azithromycin; Pfizer Brand of Azithromycin Dihydrate; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase; Play; Preclinical Drug Evaluation; Property; Property, LOINC Axis 2; Protocols, Treatment; RGM; RNA; RNA Expression; RNA, Messenger; RNA, Non-Polyadenylated; RNA-Protein Interaction; Regimen; Reporter; Research; Resistance; Ribonucleic Acid; Role; STTR; Screening procedure; Series; Small Business Technology Transfer Research; Staging; Structure; Structure-Activity Relationship; System; System, LOINC Axis 4; Systematics; Testing; Thiophenes; Toxic effect; Toxicities; Transcription; Transcription, Genetic; Translating; Translatings; Translations; Treatment Protocols; Treatment Regimen; Treatment Schedule; Ultreon; Vendor; Viral; Viral Diseases; Virus; Virus Diseases; Virus-HIV; Viruses, General; Work; Zithromax; Zitromax; Zyvox; analog; base; candidate selection; chemical structure function; chemical synthesis; combat; cultured cell line; design; designing; drug discovery; drug/agent; heavy metal Pb; heavy metal lead; human T cell leukemia virus III; human T lymphotropic virus III; in vitro Assay; inhibitor; inhibitor/antagonist; language translation; lead series; mRNA; novel; pharmacophore; protein complex; public health relevance; pyridine; resistant; rev Protein; scaffold; scaffolding; screening; screenings; small molecule; social role; structure function relationship; thienopyridine; viral infection; virus infection
