Mechanism and Inhibition of HIV Reverse Transcriptase

HIV逆转录酶的作用机制及抑制

• 批准号: 10082250
• 负责人: Karen S. Anderson
• 金额: $ 74.27万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-26 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10082250
• 关键词: AIDS therapy; Acquired Immunodeficiency Syndrome; Antiviral Agents; Centers for Disease Control and Prevention (U.S.); Cessation of life; Combined Modality Therapy; DNA; Development; Diagnosis; Disease; Drug Combinations; Drug Targeting; Drug resistance; Etiology; Face; Family; Genome; HIV; HIV Protease; HIV drug resistance; HIV-1; Human; Individual; Infection; Life; Life Cycle Stages; Mediating; Mitochondria; Molecular; Molecular Target; Mutation; Pharmaceutical Preparations; Pharmacology; Polymerase; Property; RNA; RNA-Directed DNA Polymerase; Regimen; Reporting; Resistance; Resistance profile; Safety; Structure; Therapeutic; Toxic effect; Variant; Viral; World Health Organization; antiretroviral therapy; clinically relevant; combat; design; drug development; effective therapy; improved; inhibitor/antagonist; lead candidate; lead optimization; member; mouse model; nanoformulation; non-nucleoside reverse transcriptase inhibitors; novel; novel drug combination; novel lead compound; novel therapeutic intervention; novel therapeutics; nucleoside inhibitor; pre-clinical; resistant strain; side effect; socioeconomics; synergism

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.

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，其中包含一个单一的 滞留的RNA基因组，是与获得开发有关的主要病因 免疫缺陷综合征或艾滋病。世界卫生组织现在估计，2016年超过40 全世界有百万人被感染。最新的CDC报告估计，在美国，超过120万 人们被感染了，其中包括大约13％的人不知道自己的感染。随着 抗逆转录病毒疗法（ART），过去十年来一直取得了很多进展。不断的 耐药性艾滋病毒变体的出现和生命长期治疗的副作用需要发展 新疗法。开发可能也有效的组合疗法也将非常有益。 HIV病毒的生命周期中有许多潜在靶标，包括HIV逆转录酶 （RT），HI​​V蛋白酶，以及最近的病毒输入，依恋和整合。靶向RT的药物仍然是 大多数治疗方案中艾滋病治疗的基石。靶向HIV-1 RT的药物分为两个 类：核苷抑制剂（NRTIS）和非核苷抑制剂（NNRTIS）。药物的快速发展 易于误差RT的抗性，副作用以及病毒式与宿主聚合酶选择性的问题，需要 发现更有效的NRTI和NNRTI，具有改善的安全性，药理和耐药性 概况。建立在发现非常有效的新型铅化合物的基础上，使用计算，机制， 以及结构指导的设计，PI和一组已建立的合作者，已使用铅优化来 开发三个新的新型nnrtis。这些新的nnrtis在WT和药物方面具有出色的效力 HIV的抗性菌株，最佳药理学特性，与临床相关的NRTI和功效的协同作用 在AIDS HU-MOUSE模型中。描述了将这些化合物发展为临床前的综合研究 可能也可以在联合疗法中有用的候选人。