New Non-Nuceleotide Reverse Transcriptase Inhibitors for Drug Resistant HIV Strains

用于耐药 HIV 菌株的新型非核苷酸逆转录酶抑制剂

• 批准号: 10452754
• 负责人: Chin-Ho Chen
• 金额: $ 50.92万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-16 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452754
• 关键词: AIDS/HIV problem; Affinity; Amino Acids; Anti-Retroviral Agents; Antiviral Agents; Binding; Biological Assay; Biological Testing; Chemicals; Clinical Drug Development; Clinical Treatment; Computer Assisted; Computer Models; Coupled; Crystallization; Docking; Drug Design; Drug Kinetics; Drug Targeting; Drug resistance; Effectiveness; Future; Goals; HIV; HIV drug resistance; HIV resistance; HIV-1; HIV-1 drug resistance; Hand; In Vitro; Infection; Ligands; Methodology; Modernization; Modification; Multi-Drug Resistance; Mutate; Mutation; NNRTI-resistance; Outcome; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Play; Positioning Attribute; Preclinical Drug Development; Property; Research; Resistance; Resistance development; Resistance profile; Reverse Transcriptase Inhibitors; Role; Structure; System; Techniques; Testing; Variant; Viral; Virus; Work; antiretroviral therapy; base; chemical synthesis; design; drug candidate; drug development; drug discovery; drug resistant virus; drug structure; fitness; improved; indexing; lead optimization; meetings; molecular modeling; mouse model; mutant; non-nucleoside reverse transcriptase inhibitors; resistance mutation; screening; success

Abstract Antiretroviral therapy (ART) for HIV/AIDS is effective in the clinical treatment of HIV-1 infections. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a class of anti-retrovirals playing a major role in the success of ART. However, the emergence of drug resistant viruses has limited the usefulness of the NNRTIs in many patients. Thus, new NNRTIs are needed to overcome current NNRTI resistant HIV strains. The goal of this study is to identify new NNRTIs effective for drug resistant viruses. We have previously discovered two classes of NNRTIs, diarylanilines (DAANs) and diarylpyridinamines (DAPAs), which are structurally different from the approved diarylpyrimidine (DAPY)-type drugs etravirine and rilpivirine. Each of the chemical classes can fully overcome some prevalent NNRTI resistant mutations. However, none of them was effective for all the prevalent NNRTI resistant HIV-1 variants. To fully overcome the NNRTI resistance, we have identified the key structural features from each of the chemical classes that are required for effectiveness against drug resistant viruses. We hypothesize that a compound with structural features effective for drug resistant viruses can be synthesized and will be effective for viruses resistant to current NNRTIs. To test our hypothesis and to accomplish our goal, we propose to carry out the following two Specific Aims. Aim 1 is to design and synthesize new diarylaniline (DAAN) and diarylpyridinamine (DAPA) derivatives to overcome HIV-1 variants resistant to NNRTIs. This aim will be achieved by designing new NNRTIs that include favorable structural features for overcoming drug resistance selected from DAANs/DAPAs. Aim 2 is to establish the pharmacological profiles of the new NNRTIs effective against drug resistant HIV-1. The pharmacological study is aimed at establishing basic/initial pharmacological profiles to pave the way for future more comprehensive drug-target interaction studies and clinical drug development. Achieving this aim will provide the essential information to advance the compounds for further preclinical drug development to mitigate NNRTI resistance. Our chemical synthesis will be supported by conventional medicinal chemistry and modern molecular modeling. The lead optimization will be guided by well- established primary and secondary biological testing against wild-type and NNRTI resistant virus, respectively. The research team is positioned uniquely to conduct this endeavor based on over two decades of anti-HIV research. With confirmed promising leads already on-hand, coupled with the availability of established bioassay systems, we feel confident that we can discover and develop new NNRTIs to overcome the prevalent NNRTI resistant viruses.

抽象的 HIV/AIDS 的抗逆转录病毒治疗 (ART) 在 HIV-1 感染的临床治疗中是有效的。非核苷类 逆转录酶抑制剂（NNRTI）是一类抗逆转录病毒药物，在治疗成功中发挥着重要作用。 艺术。然而，耐药病毒的出现限制了 NNRTI 在许多领域的用途。 患者。因此，需要新的 NNRTI 来克服目前对 NNRTI 耐药的 HIV 病毒株。本研究的目标 目的是鉴定对耐药病毒有效的新 NNRTI。我们之前发现了两类 NNRTI、二芳基苯胺 (DAAN) 和二芳基吡啶胺 (DAPA) 的结构与 批准的二芳基嘧啶（DAPY）类药物依曲韦林和利匹韦林。每个化学类别都可以充分 克服一些常见的 NNRTI 耐药突变。然而，它们中没有一个对所有流行的疾病都有效。 NNRTI 抗性 HIV-1 变体。为了完全克服 NNRTI 耐药性，我们已经确定了关键的结构 有效对抗耐药病毒所需的每种化学类别的特征。我们 假设可以合成具有对耐药病毒有效的结构特征的化合物，并且 对现有 NNRTI 具有抗药性的病毒有效。为了检验我们的假设并实现我们的目标，我们 建议实现以下两个具体目标。目标1是设计和合成新型二芳基苯胺（DAAN） 和二芳基吡啶胺 (DAPA) 衍生物，以克服对 NNRTI 耐药的 HIV-1 变异体。这个目标将是 通过设计新的 NNRTI 来实现，其中包含克服耐药性的有利结构特征 从 DAAN/DAPA 中选择。目标 2 是建立有效的新 NNRTI 的药理学特征 对抗耐药性 HIV-1。药理学研究旨在建立基础/初步药理学 为未来更全面的药物-靶点相互作用研究和临床药物铺平道路 发展。实现这一目标将为进一步推进化合物提供必要的信息。 减轻 NNRTI 耐药性的临床前药物开发。我们的化学合成将得到以下支持 传统药物化学和现代分子建模。先导化合物优化将由良好的指导 分别针对野生型和 NNRTI 抗性病毒建立了初级和次级生物学测试。 该研究团队在开展这项工作方面处于独特的地位，其基础是二十多年的抗艾滋病毒研究成果 研究。已有已确认的有前景的线索，再加上已建立的生物测定的可用性 系统，我们有信心能够发现和开发新的 NNRTI 来克服流行的 NNRTI 抗性病毒。