Mechanism and Inhibition of HIV Reverse Transcriptase

项目摘要/摘要 HIV-1(人类免疫缺陷病毒)是逆转录病毒家族的成员，它包含一种单一的- 核糖核酸基因组，是获得性肺炎发生的主要病原体。 免疫缺陷综合症或艾滋病。世界卫生组织现在估计，2016年有超过40人 全球有100万人受到感染。美国疾病控制与预防中心的最新报告估计，美国有超过120万人 人们被感染，其中约13%的人没有意识到自己的感染。随着……的发展 在抗逆转录病毒疗法(ART)方面，在过去十年中取得了亟需的进展。持续不断的 耐药艾滋病毒变异株的出现和终身治疗的副作用使发展成为必然 新的疗法..开发可能也有效的联合疗法也是非常有益的。 在艾滋病毒的生命周期中有一些潜在的目标，包括艾滋病毒逆转录酶 (RT)、HIV蛋白水解酶，以及最近的病毒进入、附着和整合。靶向RT的药物仍然是一种 在大多数治疗方案中，艾滋病治疗的基石。针对HIV-1RT的药物分为两种 分类：核苷抑制剂(NRTI)和非核苷抑制剂(NNRTI)。药品的快速发展 容易出错的RT产生的耐药性、副作用以及病毒对宿主聚合酶的选择性问题使我们有必要 发现更有效的NRTI和NNRTI，具有更好的安全性、药理学和耐药性 配置文件。建立在发现一种非常有效的新型先导化合物的基础上，通过计算，机制， 和结构指导的设计，PI和一组既定的合作者使用了Lead优化来 开发三类新型NNRTI。这些新的NNRTI在治疗WT和药物方面具有很好的效力 HIV耐药株，最佳药理特性，与临床相关NRTI的协同作用，以及疗效 在艾滋病人鼠模型中。描述了将这些化合物开发为临床前的综合研究。 在联合治疗中也可能有用的候选人。

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.