In vivo Consequences of VIf anatgonism

VIf 拮抗作用的体内后果

基本信息

批准号：
8271414
负责人：
KEITH G. MANSFIELD
金额：
$ 32.94万
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：
2011
资助国家：
美国
起止时间：
2011-04-28 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8271414
关键词：
AIDS Dementia Complex AIDS neuropathy Biological Markers Cardiomyopathies Cells Clinical Deamination Development Disease Dose Drug Delivery Systems Drug Kinetics Evolution Goals HIV HIV Infections HIV-1 Highly Active Antiretroviral Therapy Immunologic Deficiency Syndromes Incidence Individual Inflammation Inflammatory Intervention Lead Macaca Macaca mulatta Massachusetts Metabolic Modeling Molecular Virology Pathology Peripheral Pharmaceutical Chemistry Pharmaceutical Preparations Plasma Preclinical Drug Evaluation Process Proteins Quality of life Rodent Route SIV SIV encephalitis Safety System Therapeutic Toxic effect Universities Viral Viral Genes Viral Load result Viral Markers Work World Health Organization base drug candidate human morbidity human mortality improved in vivo inhibitor/antagonist medical schools nonhuman primate novel pre-clinical small molecule small molecule libraries vaccine development vif Gene Products viral DNA viral resistance

项目摘要

In this application we propose the development of small molecule inhibitors of the HIV Vif protein. While Vif has been recognized as an important gene for viral infectivity, the cellular mechanism responsible for this effect has only recently been elucidated. Vif functions to inactivate the cellular defense protein APOBEC 3G which otherwise induces deamination of viral DNA rendering it noninfectious. Our previous work in vaccine development has demonstrated the crucial in vivo significance of Vif to viral replication in the rhesus macaque and supports the relevance of this drug target. The University of Massachusetts Medical School (UMMS) established a high throughput drug screening facility in order to identify lead compounds with activity against HIV/SIV Vif. As part of this venture, a large chemical library has been screened for anti-Vif compounds using a cell-based inhibitor screen and a number of lead compounds have been identified that have the potential to target peripheral and CNS reservoirs of HIV-1 replication and persistence. The proposed work will facilitate the further development of these Vif inhibiting agents. The application brings together a collaborative team with diverse expertise in medicinal chemistry, molecular virology, and in vivo systems to examine the clinical potential of such inhibitors. Our objective is to utilize pharmacokinetic and efficacy studies in rodent species in a lead optimization approach reserving proof-of-principal studies in nonhuman primates to the most promising drug candidates. Long term efficacy studies will allow us to examine the effect of Vif inhibitors on plasma viral load and markers of immunodeficiency as well as to evaluate the effect of drug treatment on SIV encephalitis, a lentiviral specific disease process. To accomplish these goals we propose the following specific aims: Specific aim 1: To define the pharmacokinetic and safety profile of novel Vif inhibitors in rodents and rhesus macaques. Specific aim 2: To examine the short term in vivo effect of Vif inhibitors on viral replication and cellular reservoirs in rodent and rhesus macaque models of HIV infection. Specific aim 3: To examine the efficacy of Vif inhibitors on biomarkers of CNS inflammation and morphologic evidence of CNS pathology in an SIV-macaque model of neuroAIDS.

在此应用中，我们建议开发 HIV Vif 蛋白的小分子抑制剂。虽然 Vif 已被认为是病毒感染性的重要基因，但其细胞机制直到最近才阐明了造成这种影响的原因。 Vif 具有灭活细胞活性的作用防御蛋白 APOBEC 3G，否则会诱导病毒 DNA 脱氨，从而使其脱氨无传染性。我们之前在疫苗开发方面的工作已经证明了体内关键的 Vif 对恒河猴病毒复制的重要性并支持该药物的相关性目标。马萨诸塞大学医学院（UMMS）建立高通量药物筛选设施，以确定具有抗 HIV/SIV Vif 活性的先导化合物。作为本次活动的一部分风险投资，使用基于细胞的抑制剂筛选了一个大型化学库中的抗 Vif 化合物筛选和许多先导化合物已被鉴定出有可能靶向外周 HIV-1复制和持久性的中枢神经系统储存库。拟议的工作将有利于进一步这些 Vif 抑制剂的开发。该应用程序汇集了一个协作团队药物化学、分子病毒学和体内系统方面的不同专业知识来检查临床此类抑制剂的潜力。我们的目标是在啮齿动物物种中率先利用药代动力学和功效研究优化方法将非人类灵长类动物的原理验证研究保留给最有前途的候选药物。长期疗效研究将使我们能够检查 Vif 抑制剂对血浆的影响病毒载量和免疫缺陷标志物以及评估药物治疗对 SIV 的效果脑炎，一种慢病毒特异性疾病过程。为了实现这些目标，我们提出以下建议具体目标：具体目标 1：确定新型 Vif 抑制剂在啮齿类动物中的药代动力学和安全性和恒河猴。具体目标 2：检查 Vif 抑制剂对病毒复制和病毒复制的短期体内影响 HIV感染的啮齿动物和恒河猴模型中的细胞储存库。具体目标 3：检查 Vif 抑制剂对 CNS 炎症和生物标志物的功效神经艾滋病 SIV 猕猴模型中 CNS 病理学的形态学证据。