Preclinical Development of HIV-1 Vif Antagonists - Project 2

HIV-1 Vif 拮抗剂的临床前开发 - 项目 2

• 批准号: 8723304
• 负责人: Mario Stevenson
• 金额: $ 30.55万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8723304
• 关键词: AIDS neuropathy; Antiviral Agents; Attenuated; Biological Assay; Cell Line; Cells; Data; Defective Viruses; Development; Drug Kinetics; Evaluation; Exercise; Exhibits; Goals; Grant; HIV-1; In Vitro; Individual; Inhibitory Concentration 50; Instruction; Lead; Lymphoid; Macaca; Modeling; Monkeys; Mutation; Pathogenicity; Penetration; Peripheral; Phenotype; Plasma; Research; Research Personnel; Resistance; Resistance profile; Resources; SIV; Serial Passage; Series; Toxic effect; Variant; Viral; Virus; Water; analog; cellular targeting; design; drug discovery; in vivo; inhibitor/antagonist; insight; macrophage; mutant; novel; pre-clinical; programs; resistance mutation; response; small molecule; vif Gene Products; vif Genes; viral RNA

PROJECT SUMMARY (See Instructions): _ This program project application comprises a team of investigators with complimentary research strengths and resources that will be harnessed for the development of novel small molecules that antagonize the action of the HIV-1 vif protein. Project 2 (Virologic support for SAR and mechanisms of inhibitor resistance) will predominantly support drug discovery/SAR efforts in Project 1 as well as identifying mutations conferring inhibitor resistance in vitro and in vivo. Specific responsibilities of Project 2 include: ¿ Evaluation of antiviral activity of lead compounds and their analogs in permissive and non-permissive cells. The antiviral activities of analogs emerging from the SAR exercise of Project 1 will be compared in permissive cells (vif-independent replication) and non-permissive cells (vif-dependent replication) and will be used to drive the design of analogs with more potent antiviral activity. ¿ Evaluation of antiviral activity in primary cells relevant to CNS reservoirs of viral replication. Macrophage are the principle cellular targets in the CNS and infected macrophage drive the neuropathogenic manifestations of viral replication. Therefore, vif antagonists will be evaluated for antiviral activity in primary macrophage in vitro. ¿ Identification of mechanisms governing inhibitor resistance in vitro and in vivo. HIV-1 will be passaged in non-permissive cells in increasing concentrations of prioritized Vif analogs in order to derive inhibitor resistant virus. In addition, plasma viral RNA from inhibitor-treated macaques (Project 3) will be cloned and sequenced to identify mutations conferring resistance in vivo. Impact of vif-inhibitor resistance on sensitivity to other ARV classes will be conducted with Core B. The virologic studies outlined in Project 2 will guide the SAR studies and drive the prioritization of analogs that go forward for analysis of in vivo efficacy in macaques.

项目摘要（请参阅说明）：_ 该计划的项目应用程序包括一个研究人员，具有免费的研究优势和资源，该团队将用于开发新型的小分子，从而拮抗HIV-1 VIF蛋白的作用。项目2（对SAR的病毒学支持和抑制剂耐药性机制）将主要支持项目1中的药物发现/SAR努力，并确定突变会议会议会议在体外和体内抑制剂耐药性。项目2的具体责任包括： »评估铅化合物的抗病毒活性及其在允许和非允许细胞中的类似物。 从项目1的SAR练习中出现的类似物的抗病毒活性将进行比较 允许的细胞（独立于VIF的复制）和非允许细胞（VIF依赖性复制），并将用于驱动具有更多潜在抗病毒活性的类似物的设计。 »评估与病毒复制中枢神经系统储层相关的原代细胞中的抗病毒活性。巨噬细胞是中枢神经系统中的主要细胞靶标，并感染的巨噬细胞驱动病毒复制的神经病作用表现。因此，将评估VIF拮抗剂的体外原发性巨噬细胞中的抗病毒活性。 »鉴定管理抑制剂在体外和体内耐药性的机制。 HIV-1将以越来越多的优先VIF类似物浓度的非腐败细胞中通过，以导致抑制剂耐药性病毒。此外，将从抑制剂治疗的猕猴（项目3）中的血浆病毒RNA克隆并测序，以鉴定体内的突变会议抗性。 VIF抑制剂耐药性对其他ARV类别的敏感性的影响将使用CoreB进行。 项目2中概述的病毒学研究将指导SAR研究，并推动类似物的优先级，这些类似物向前迈进，以分析猕猴的体内效率。