Rational Design of NRTI for Drug Resistant HIV-1

针对耐药 HIV-1 的 NRTI 的合理设计

• 批准号: 7569004
• 负责人: John W Mellors
• 金额: $ 59.09万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-15 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7569004
• 关键词: Affect; Anti-Retroviral Agents; Biochemistry; Bone Marrow; Clinical; DNA; Data; Development; Drug Kinetics; Drug resistance; Excision; Exhibits; HIV-1; HIV-1 Reverse Transcriptase; HIV-1 drug resistance; Human; In Vitro; Infection; Knowledge; Lead; Mitochondria; Molecular; Molecular Models; Pharmaceutical Preparations; Pharmacology; Prodrugs; Resistance; Resistance profile; Reverse Transcriptase Inhibitors; Safety; Stem cells; Structure; Testing; Toxic effect; Variant; analog; base; design; improved; insight; meetings; molecular modeling; novel; nucleoside analog; resistance mechanism; tripolyphosphate; virology

DESCRIPTION (provided by applicant): Nucleoside analog reverse transcriptase inhibitors (NRTI) are integral components of therapy for HIV-1 infection. The currently approved NRTI have significant limitations that include short- and long-term toxicity, pharmacokinetic interactions with other antiretroviral drugs, and the selection of drug-resistant HIV-1 variants that are cross-resistant with other NRTI. Accordingly, there is a critical need to develop new NRTI that have excellent activity and safety profiles and exhibit little or no cross-resistance with existing drugs. We hypothesize that the rational design of NRTI, based on knowledge of both resistance mechanisms and structural components of NRTI that affect sensitivity to these resistance mechanisms, represents the best strategy to identify new NRTI that are active against drug resistant HIV-1. Using data derived from such structure-activity-resistance studies, we have identified a lead class of compounds, the 3'-azido-2',3'- dideoxypurines (ADPs), that retain potent activity against many drug-resistant variants of HIV-1. These include drug-resistant variants that (i) improve the ability of HIV-1 reverse transcriptase to discriminate between the natural dNTP substrate and the NRTI-triphosphate, and (ii) enhance the excision of the chain- terminating NRTI-monophosphate from the prematurely terminated DNA chain. In this application, we propose in-depth studies of structure-activity-resistance relationships, intracellular pharmacology, toxicity, and resistance selection to identify the most promising clinical candidates from the ADP class. This will be accomplished through three Specific Aims. In Aim 1, we will synthesize additional, novel ADP analogs, and prodrugs thereof, to optimize potency against both wild-type and NRTI-resistant HIV-1. In Aim 2, the ADPs that demonstrate favorable anti-HIV-1 activity and cross-resistance profiles will be further characterized by testing their potential toxicity toward human mitochondria and bone marrow progenitor cells. In Aim 3, we will select and characterize HIV-1 variants that are resistant to the ADPs, and elucidate the molecular mechanism(s) by which resistance is conferred. The identification and development of the novel ADPs through the rational design and assessments proposed in this application could help meet the expanding need for potent and safe NRTI that are active against drug-resistant HIV-1.

描述（由申请人提供）：核苷类似物逆转录酶抑制剂（NRTI）是HIV-1感染治疗的组成部分。当前批准的NRTI具有重大局限性，包括短期和长期毒性，与其他抗逆转录病毒药物的药代动力学相互作用以及与其他NRTI交叉耐药的耐药性HIV-1变体的选择。因此，迫切需要开发具有出色活性和安全性的新NRTI，并且与现有药物几乎没有或没有交叉抗性。我们假设NRTI的理性设计基于对影响对这些抗性机制敏感性的NRTI的抗性机制和结构成分的了解，这是识别具有抗药性HIV HIV-HIV-HIV-HIV-1的新NRTI的最佳策略。使用从这种结构抗性研究得出的数据，我们已经确定了铅类化合物，即3'-azido-2'，3'-二维氧化胺（ADP），它们保留了许多HIV-1的耐药性变体的有效活性。其中包括（i）提高HIV-1逆转录酶区分自然DNTP底物和NRTi-Triph磷酸盐的能力，以及（ii）增强链式终止NRTI-单磷酸链链中的NRTI-单磷酸与质量终止DNA链的切除。在此应用中，我们提出了对结构性抗性关系，细胞内药理学，毒性和耐药性选择的深入研究，以确定ADP类中最有希望的临床候选者。这将通过三个具体目标来实现。在AIM 1中，我们将合成其他新型的ADP类似物及其前药，以优化针对野生型和NRTI耐药的HIV-1的效力。在AIM 2中，表现出有利的抗HIV-1活性和交叉抗性曲线的ADP将通过测试其对人线粒体和骨髓祖细胞的潜在毒性的进一步特征。在AIM 3中，我们将选择并表征对ADP抗性的HIV-1变体，并阐明赋予电阻的分子机制。通过本申请中提出的合理设计和评估对新ADP的识别和开发可能有助于满足对耐药性HIV-1有效的有效NRTI的不断增长的需求。