Structure activity and structure property relationships for novel anti-HIV agents

新型抗HIV药物的结构活性和结构性质关系

基本信息

批准号：
8777085
负责人：
Kathleen Mary Frey
金额：
$ 4.14万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-12-01 至 2015-08-21
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8777085
关键词：
Acquired Immunodeficiency Syndrome Adverse effects Affinity Animal Model Anti-HIV Agents Antiviral Agents Binding Biological Assay Biological Availability CYP3A4 gene Caco-2 Cells Catechols Cellular Assay Complex Computer Simulation Computing Methodologies Crystallization Crystallography Data Development Docking Drug Design Drug Interactions Drug Kinetics Drug Targeting Drug resistance Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Epidemic Equilibrium FDA approved Future Genome HIV HIV-1 Half-Life Health High Pressure Liquid Chromatography Highly Active Antiretroviral Therapy In Vitro Individual Infection Integrase Inhibitors Kinetics Knowledge Lead Libraries Link Liver Microsomes Measurement Measures Metabolic Methods Modeling Modification Molecular Models Mutation Nevirapine Nucleosides Nucleotides Patients Permeability Pharmaceutical Preparations Phase Plasma Process Property Protease Inhibitor Quality of life RNA-Directed DNA Polymerase Research Resistance Resistance profile Reverse Transcriptase Inhibitors Safety Series Solubility Structure Structure-Activity Relationship System Techniques Therapeutic Therapeutic Index Toxic effect Treatment Failure Uracil Variant Viral Viral Load result Virus Diseases Work base computational chemistry cytotoxicity design drug candidate drug development drug discovery ds-DNA efavirenz effective therapy improved in vitro Assay inhibitor/antagonist lipophilicity molecular modeling mutant novel novel therapeutics polymerization resistance mutation scaffold small molecule viral RNA

项目摘要

DESCRIPTION (provided by applicant): Reverse transcriptase (RT) is an essential enzyme that copies the viral RNA genome into double stranded DNA via polymerization, a process required for HIV-1 infection. Several enzymes in HIV-1, including RT, are drug targets for highly active antiretroviral therapies (HAART). Non-nucleoside and non-nucleotide RT inhibitors (NNRTIs) are therapeutics prescribed in combination with 3-4 additional antiviral agents that work synergistically to induce viral load suppression in infected patients. Currently, there are fie FDA approved NNRTIs targeting RT, which include nevirapine, delaviridine, efavirenz, etravirine, and rilpivirine. However, there are several limitations to current NNRTIs such as resistance and toxicity issues from long-term usage. The design and development of new NNRTIs with improved resistance and safety profiles is crucial to overcome HIV-1 treatment failure. Over the last few years, we have developed several new compounds as potential NNRTIs using a combination of mechanistic studies, computational chemistry, and structure-based drug design. We have recently designed an NNRTI compound that is active against HIV-1 and has a therapeutic index of 180,000 for cellular toxicity. With an EC50 of 55 pM, this compound emerges as the most potent antiviral agent targeting HIV-1 to date. In order to optimize these compounds into potential drug candidates, this proposal aims to develop structure activity relationships (SAR) and structure property relationships (SPR). Pre-steady state kinetics will determine binding affinity measurements for leading NNRTI compounds and the RT enzyme. In addition to binding affinities, co-crystallization of leading NNRTIs and the RT enzyme will provide a structural interpretation for enzyme-inhibitor interactions and SAR. A series of in vitro analytical and pharmacological techniques will be used to determine SPR for leading compounds. Structure property measurements to be determined include lipophilicity, kinetic solubility, permeability, and metabolic stability. The combination of both SAR and SPR for leading NNRTI compounds will prioritize future development and provide structural information for rational drug design of efficacious NNRTIs.

描述（由申请人提供）：逆转录酶（RT）是一种必不可少的酶，将病毒RNA基因组复制为双链DNA通过聚合，这是HIV-1感染所需的过程。 HIV-1中的几种酶，包括RT，是高度活性抗逆转录病毒疗法（HAART）的药物靶标。非核苷和非核苷酸RT抑制剂（NNRTIS）与3-4种其他抗病毒药物结合使用，这些抗病毒剂协同起作用，可在受感染的患者中诱导病毒载荷抑制。当前，有FIE FDA批准的NNRTIS靶向RT，其中包括Nevirapine，Delaviridine，Efavirenz，Etravirine和Rilpivirine。但是，目前的nnrtis有几个局限性，例如长期使用的抗性和毒性问题。具有提高阻力和安全性概况的新NNRTI的设计和开发对于克服HIV-1治疗失败至关重要。在过去的几年中，我们使用机械研究，计算化学和基于结构的药物设计的组合开发了几种新化合物作为潜在的NNRTIS。我们最近设计了一种针对HIV-1的NNRTI化合物，其治疗指数为180,000，用于细胞毒性。 EC50为55 pm，该化合物是迄今为止针对HIV-1的最有效的抗病毒剂。为了将这些化合物优化到潜在的候选药物中，该建议旨在发展结构活动关系（SAR）和结构财产关系（SPR）。稳态的状态动力学将确定铅NNRTI化合物和RT酶的结合亲和力测量值。除了结合亲密关系外，领先的NNRTI和RT酶的共结晶还将为酶抑制剂相互作用和SAR提供结构性解释。一系列体外分析和药理技术将用于确定铅化合物的SPR。待确定的结构特性测量包括亲脂性，动力学溶解度，渗透性和代谢稳定性。 SAR和SPR用于领先的NNRTI化合物的组合将优先考虑未来的开发，并为有效的NNRTIS的合理药物设计提供结构信息。