Mechanism and Inhibition of HIV Reverse Transcriptase

HIV逆转录酶的作用机制及抑制

• 批准号: 10407019
• 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/10407019
• 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; Persons; 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; 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; pre-clinical assessment; 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.

项目概要/摘要 HIV-1（人类免疫缺陷病毒）是逆转录病毒家族的一员，包含一个单 链RNA基因组是参与获得性遗传病发展的主要病原体 免疫缺陷综合症或艾滋病。世界卫生组织目前估计，2016 年有超过 40 全球有数百万人被感染。 CDC 的最新报告估计，美国有超过 120 万 人们被感染，其中约 13% 的人不知道自己被感染。随着发展 抗逆转录病毒疗法（ART）在过去十年中取得了急需的进展。持续的 HIV 耐药性变异的出现和终身治疗的副作用使得开发成为必要 新疗法的开发。开发可能有效的联合疗法也将非常有益。 HIV病毒的生命周期中有许多潜在的靶标，包括HIV逆转录酶 (RT)、HIV 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 大多数治疗方案中艾滋病治疗的基石。靶向HIV-1 RT的药物分为两类 类别：核苷抑制剂（NRTI）和非核苷抑制剂（NNRTI）。药物的快速发展 容易出错的 RT、副作用以及病毒与宿主聚合酶选择性问题导致的耐药性需要 发现更有效的 NRTI 和 NNRTI，并提高安全性、药理学和耐药性 配置文件。在发现一种非常有效的新型先导化合物的基础上，利用计算机制， 和结构引导设计、PI 和一组既定的合作者，已使用先导优化来 开发三类新的新型 NNRTI。这些新的 NNRTI 对 WT 和药物具有出色的效力 HIV 耐药株、最佳药理学特性、与临床相关 NRTI 的协同作用以及功效 在艾滋病人鼠模型中。描述了将这些化合物开发为临床前药物的综合研究 可能也可用于联合治疗的候选者。