Mechanism and Inhibition of HIV Reverse Transcriptase

项目总结/摘要 HIV-1（人类免疫缺陷病毒）是逆转录病毒家族的一员，它包含一个单一的- 链的RNA基因组，是主要的病原体参与的发展，获得性 免疫缺陷综合征或艾滋病。世界卫生组织估计，2016年， 全世界有数百万人被感染。最新的CDC报告估计，在美国， 受感染的人，包括约13%不知道自己感染的人。的发展 在抗逆转录病毒疗法（ART）方面，过去十年来取得了急需的进展。不断 抗药性艾滋病毒变异体的出现和终身治疗的副作用需要开发 新疗法..开发可能也有效的联合疗法也是非常有益的。 在HIV病毒的生命周期中有许多潜在的靶点，包括HIV逆转录酶 (RT)、艾滋病毒蛋白酶，以及最近的病毒进入、附着和整合。靶向RT的药物仍然是 是大多数治疗方案中艾滋病治疗的基石。针对HIV-1 RT的药物分为两种 类别：核苷抑制剂（NRTI）和非核苷抑制剂（NNRTI）。药物的快速发展 由易错RT产生的耐药性、副作用以及病毒与宿主聚合酶选择性的问题使得 发现更有效的NRTI和NNRTI，具有更好的安全性、药理学和耐药性 数据区.在发现一种非常有效的新型先导化合物的基础上，使用计算机制， 和结构导向设计，PI和一组既定的合作者，使用铅优化， 开发三种新型NNRTI。这些新的非核苷类逆转录酶抑制剂对野生型和药物具有良好的效力。 HIV耐药株、最佳药理学特性、与临床相关NRTI的协同作用和疗效 在艾滋病小鼠模型中。描述了将这些化合物开发成临床前的全面研究。 也可能在联合治疗中有用的候选物。

PROJECT SUMMARY / ABSTRACT The HIV-1 (Human Immunodeficiency Virus) is a member of the retroviral family which contains a single- stranded RNA genome and is the major etiological agent involved in the development of acquired immunodeficiency syndrome or AIDS. The World Health Organization now estimates that in 2016 over 40 million people worldwide are infected. The most recent CDC report estimates that in the US over 1.2 million people are infected including about 13% who are unaware of their infections. With the development of antiretroviral therapy (ART), there has been much needed progress over the past decade. The continual emergence of drug resistance HIV variants and side effects of life long therapy necessitates the development of new therapies.. Developing combination therapies that might also be effective would also be very beneficial. There are a number of potential targets in the life cycle of the HIV virus including HIV reverse transcriptase (RT), HIV protease, and more recently viral entry, attachment, and integration. Drugs targeting RT remain a cornerstone of AIDS therapy in most therapeutic regimens. The drugs that target HIV-1 RT are divided into two classes: nucleoside inhibitors (NRTIs) and non-nucleoside inhibitors (NNRTIs). The rapid development of drug resistance by the error prone RT, side effects, and issues of viral vs host polymerase selectivity necessitate the discovery of more effective NRTIs and NNRTIs with improved safety, pharmacological, and drug resistance profiles. Building on the discovery of a very potent novel lead compound, using computationally, mechanism, and structure-guided design, the PI and an established set of collaborators, have used lead optimization to develop three new classes of novel NNRTIs. These new NNRTIs have excellent potency on WT and drug resistant strains of HIV, optimal pharmacological properties, synergy with clinically relevant NRTIs, and efficacy in AIDS hu-mouse models. Comprehensive studies are described to develop these compounds into preclinical candidates that might also be useful in combination therapy.