Structure-Based Development of nonnucleoside anti-HIV-1 RT Drugs

非核苷类抗 HIV-1 RT 药物的基于结构的开发

基本信息

批准号：
7802045
负责人：
Virendra Nath PANDEY
金额：
$ 23.62万
依托单位：
UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-10 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7802045
关键词：
Acquired Immunodeficiency Syndrome Address Anti-HIV Agents Antiviral Agents Binding CD4 Positive T Lymphocytes Cell Culture Techniques Chemical Structure Cleaved cell Clinical Complex DBL Oncoprotein DNA-Directed DNA Polymerase Development Docking Drug resistance Enzymes Evaluation Fingers HIV HIV drug resistance HIV-1 HIV-1 Reverse Transcriptase In Vitro Infection Laboratories Lead Ligands Methods Modification Molecular Models Nevirapine Nucleosides Pharmaceutical Preparations Pharmacotherapy Polymerase Positioning Attribute Preparation Pyridones RNA-Directed DNA Polymerase Retroviridae Reverse Transcriptase Inhibitors Screening procedure Side Site Structure Therapeutic Intervention Thumb structure Variant Viral Virion Virus Virus Diseases Zidovudine base chemotherapeutic agent combat cytotoxicity design drug resistant virus drug sensitivity improved in vitro Assay in vitro Model indexing inhibitor/antagonist molecular modeling mutant non-nucleoside reverse transcriptase inhibitors nucleoside inhibitor particle pharmacophore pressure resistance mechanism

项目摘要

DESCRIPTION (provided by applicant): HIV-1 RT is a key enzyme responsible for viral replication and subsequent perpetuation of viral infection. Hence, it has been the primary target for therapeutic intervention against HIV-1 infection. However, rapid emergence of drug-resistant viral strains harboring enzymatically-active mutant RT with reduced drug-sensitivity has frustrated all efforts to control the spread of HIV-1 infection. The mechanism of resistance to nucleoside inhibitors seems to be quite complex since a number of mutational sites do not cluster around the putative dNTP-binding pocket in the polymerase cleft. However, for nonnucleoside RT inhibitors (NNRTIs), a common hydrophobic binding region is seen in the crystal structures of RT liganded with these inhibitors. The side chains of a number of hydrophobic residues located in the fingers, palm and thumb subdomains in the p66 subunit converge to form a hydrophobic NNRTI binding pocket. Any mutational change in these hydrophobic residues reduces the drug-sensitivity due to alteration in the NNRTI-binding pocket. Our proposal seeks to address this problem by developing a group of new NNRTIs which are effective against both the wild type and common drug-resistant variants of HIV-1 RT. Using a combination of structure-based molecular modeling and in vitro assays, we have selected four distinct lead compounds from a large repertoire of compounds displaying inhibitory activity against both wild type and mutant RT. We plan to further modify these lead compounds by a structure-based design strategy to improve their inhibitory potential followed by synthesis and in vitro anti-HIV-1 RT screening. PUBLIC HELATH RELEVANCE: The major focus of this proposal is to develop a new class of NNRTIs that is equally effective against both the wild type and drug-resistant variants of HIV-1 RT. We selected four nonnucleoside lead compounds from a large repertoire of compounds based on structure-based modeling and in vitro anti- RT activity against both the wild type HIV-1 RT and drug-resistant RT mutants. These initial lead compounds will be modified to further enhance their anti-RT activity.

描述（由申请人提供）：HIV-1 RT是导致病毒复制和随后持续病毒感染的关键酶。因此，它一直是针对HIV-1感染的治疗干预措施的主要靶标。然而，携带酶活性突变体RT的抗药性病毒菌株的快速出现，药物敏感性降低使所有努力控制HIV-1感染的扩散。对核苷抑制剂的抗性机制似乎很复杂，因为许多突变位点在聚合酶裂缝中没有聚集在假定的DNTP结合口袋周围。然而，对于非核苷RT抑制剂（NNRTI），在用这些抑制剂的RT配体的晶体结构中可以看到一个共同的疏水结构区域。位于p66亚基中的手指，棕榈和拇指子域中的许多疏水残基的侧链会聚，形成了疏水性NNRTI结合口袋。这些疏水残基的任何突变变化都会因NNRTI结合口袋的改变而降低了药物敏感性。我们的建议旨在通过开发一组新的nnrtis来解决这个问题，这些新nnrtis对HIV-1 RT的野生型和抗药性变体有效。利用基于结构的分子建模和体外测定的组合，我们从大量化合物库中选择了四种不同的铅化合物，这些化合物表现出对野生型和突变体RT的抑制活性。我们计划通过基于结构的设计策略进一步修改这些铅化合物，以提高其抑制潜力，然后通过合成和体外抗HIV-1 RT筛选。公共Helath相关性：该提案的主要重点是开发一种新的NNRTIS，对HIV-1 RT的野生型和耐药性变体同样有效。我们根据基于结构的建模和针对野生型HIV-1 RT和耐药的RT突变体的大量化合物和体外抗RT活性选择了四种非核苷铅化合物。这些初始铅化合物将被修改以进一步增强其抗RT活性。