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

描述（由申请方提供）：HIV-1 RT是一种负责病毒复制和随后病毒感染持续的关键酶。因此，它一直是针对HIV-1感染的治疗干预的主要目标。然而，携带具有降低的药物敏感性的酶活性突变RT的耐药病毒株的快速出现使控制HIV-1感染传播的所有努力都受挫。对核苷抑制剂的耐药机制似乎相当复杂，因为许多突变位点并不聚集在聚合酶裂缝中假定的dNTP结合口袋周围。然而，对于非核苷类RT抑制剂（NNRTI），一个共同的疏水性结合区被认为是在晶体结构的RT配体与这些抑制剂。位于p66亚基中的手指、手掌和拇指亚结构域中的许多疏水残基的侧链会聚以形成疏水性NNRTI结合口袋。由于NNRTI结合口袋的改变，这些疏水残基中的任何突变变化都会降低药物敏感性。我们的建议试图通过开发一组新的NNRTI来解决这个问题，这些NNRTI对HIV-1 RT的野生型和常见耐药变体都有效。我们从大量对野生型和突变型RT都显示抑制活性的化合物中选择了四种不同的先导化合物。我们计划进一步修饰这些先导化合物，化合物通过基于结构的设计策略来提高其抑制潜力，然后进行合成和体外抗HIV-1 RT筛选。 公共卫生相关性：该提案的主要重点是开发一类新的NNRTIs，对野生型和耐药的HIV-1 RT变体同样有效。我们从基于结构的建模和对野生型HIV-1 RT和耐药RT突变体的体外抗RT活性的大量化合物中选择了四种非核苷先导化合物。这些初始先导化合物将被修饰以进一步增强其抗RT活性。

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.