Virology studies of a small molecule HIV Rev inhibitor

小分子 HIV Rev 抑制剂的病毒学研究

• 批准号: 8541558
• 负责人: Robert Nakamura
• 金额: $ 27.96万
• 依托单位: ADVANCED GENETIC SYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-18 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8541558
• 关键词: Affect; Agreement; Aminoglycoside Antibiotics; Antibiotics; Antiviral Agents; Azithromycin; Biological Assay; Biotechnology; Caring; Cell Line; Cell Nucleus; Cell Survival; Cells; Cessation of life; Clinical Drug Development; Companions; Complex; Consensus; Cytoplasm; Development; Drug Targeting; Drug resistance; Elements; Enzyme-Linked Immunosorbent Assay; FDA approved; Face; Family; Funding; Genetic; Genetic Transcription; Goals; Grant; HIV; HIV therapy; Inhibitory Concentration 50; Integrase Inhibitors; Investigational Drugs; Investments; Laboratories; Lead; Linezolid; Macrolide Antibiotics; Marketing; Messenger RNA; Molecular; Monitor; Nuclear Export; Oxazolidinones; Peptide Hydrolases; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Play; Published Comment; RNA; RNA-Directed DNA Polymerase; RNA-Protein Interaction; Regimen; Request for Applications; Resistance; Role; Scientist; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Staging; Stress; Structure; System; Testing; Therapeutic; Therapeutic Index; Toxic effect; Translating; Translations; Viral; Viral Antigens; Virus; Virus Diseases; Work; analog; base; cell type; combat; drug discovery; drug resistant virus; in vivo; inhibitor/antagonist; novel; pharmacophore; pre-clinical; programs; protein complex; public health relevance; research study; response; scaffold; screening; small molecule; thienopyridine; viral resistance; virology

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：鉴于出现了对现有药物方案具有耐药性的病毒，因此对新型HIV疗法存在重大需求。HIV中的Rev-RRE蛋白-RNA相互作用在病毒mRNA从细胞核转运到细胞质中起着重要作用，在细胞质中可以翻译或包装。我们使用商业和合成的类似物（总共> 200种）进行了广泛的结构-活性（SAR）研究，并鉴定了活性所需的关键结构元件（即，基本药效团）。在一个强大的抗HIV和毒性试验小组中进行了迭代的合成和测试，产生了可获得专利的新类似物，其效力比我们最初的筛选命中高100倍，治疗指数>4000，超过了我们最初的目标。在成功完成提交研究性新药（IND）的关键里程碑后，潜在的企业合作伙伴要求我们进行病毒学实验，以充分表征分子与多种病毒分离株和细胞类型以及与目前批准的药物组合的活性。