Preclinical Development of HIV-1 Vif Antagonists

HIV-1 Vif 拮抗剂的临床前开发

基本信息

批准号：
9325570
负责人：
Mario Stevenson
金额：
$ 116.85万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-19 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9325570
关键词：
Acquired Immunodeficiency Syndrome Advanced Development Alpha Cell Animals Antiviral Agents Award Biological Assay Biological Availability Cell Line Cells Central Nervous System Diseases Complementary DNA Cytidine Deaminase Data Dependency Development Doctor of Philosophy Dose Encephalitis Evaluation Evaluation Studies Exhibits Goals HIV HIV-1 Individual Infection Institutes Lead Macaca Modeling Molecular Monkeys Mutation Neurocognitive Deficit New Agents New England Patients Peripheral Pharmacology Phenotype Primate Lentiviruses Primates Property Proteins Rana Research Research Personnel Resistance Resistance profile Rodent Role SIV Specificity Structure-Activity Relationship Therapeutic Therapeutic Intervention Toxic effect Toxicology Universities Variant Viral Viral Load result Viral Physiology Viral reservoir Virion Virus Virus Replication Water analog base cellular targeting clinical candidate drug discovery efficacy evaluation improved in vivo inhibitor/antagonist macrophage medical schools monocyte multidisciplinary neuroAIDS new therapeutic target novel novel therapeutics permissiveness preclinical development prevent programs public health relevance reconstitution research clinical testing scaffold small molecule targeted agent targeted treatment therapeutic target vif Gene Products virology water solubility

项目摘要

DESCRIPTION (provided by applicant): The objective of this program project application is to develop novel therapeutics that target CNS and peripheral reservoirs of HIV-1 replication. Under the auspices of a U19, we have identified novel small molecules that target the vif-apobec axis and that specifically inhibit vif-dependent viral replication. Structure Activity Relationship (SAR studies have identified potent analogs (IC50 <100nm) that are active in primary' macrophage, show CNS bioavailability and exhibit unique resistance profiles. We propose to build on these discoveries to optimize the activity and specificity of these small molecule vif antagonists and, on the basis of antiviral potency/specificity, Pk/Tox and resistance profiles, prioritize the most promising analogs for analysis efficacy in a SlV/macaque model of encephalitis. The individual projects and cores that constitute this program project application and their roles are as follows: Project 1. Tariq Rana, Ph.D., Sanford-Burnham Institute, Vif antagonism: lead discovery and SAR. Project 2. Mario Stevenson, Ph.D., University of Miami Medical School. Vif antagonism: Virologic support for SAR and molecular mechanisms of inhibitor resistance. Project 3. Susan Westmoreland, VMD, New England Primate Research Center. Vif antagonism: evaluation of efficacy in a macaque model of SIV-induced encephalitis. Core A, Administration. Mario Stevenson, University of Miami Medical School. Coordination of the activities of the individual components and interaction with the external Scientific Advisory Board. Core B. Agneta von Gegerfelt' Ph.D., Bioqual Inc. SIV viral load assays and small animal Pk/Tox studies. Bioqual, Inc. will serve as a non-academic core on this program project application. Studies undertaken in this program project will advance the development of a clinical candidate and set the stage for the clinical evaluation of vif antagonists as new agents for the treatment of HIV-1 infection.

描述（由申请人提供）：该计划项目应用程序的目的是开发针对HIV-1复制的CNS和外围储层的新型治疗剂。在U19的主持下，我们确定了针对VIF-APOBEC轴的新型小分子，并特别抑制VIF依赖性病毒复制。结构活性关系（SAR研究已经确定了活性在原发性巨噬细胞中的有效类似物（IC50 <100nm），显示了CNS生物利用度并具有独特的耐药性。我们建议建立这些发现以优化这些小分子VIF的活性和特异性在抗病毒效力/特异性的基础上，PK/TOX和耐药轮廓优先考虑在脑炎的SLV/猕猴模型中分析功效的最有希望的类似物。构成该计划项目应用程序及其角色的个别项目和核心如下：项目1。项目2。MarioStevenson，迈阿密大学医学院博士。 VIF拮抗：对SAR的病毒学支持和抑制剂耐药性的分子机制。项目3。新英格兰灵长类动物研究中心VMD的Susan Westmoreland。 VIF拮抗作用：评估SIV引起的脑炎的猕猴模型中的功效。核心A，管理。马里奥·史蒂文森（Mario Stevenson），迈阿密大学医学院。各个组件活动的协调以及与外部科学顾问委员会的互动。 Core B. Agneta von Gegerfelt'Ph.D. Bioqual，Inc。将在此计划项目应用程序上充当非学术核心。该计划项目进行的研究将推动临床候选者的发展，并为VIF拮抗剂作为HIV-1感染的新药物的临床评估奠定了基础。