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.

摘要 抗逆转录病毒疗法（ART）是治疗HIV-1感染的有效方法。非核苷 逆转录酶抑制剂（NNRTI）是一类抗逆转录病毒药物，在逆转录病毒治疗的成功中发挥着重要作用。 条然而，耐药病毒的出现限制了NNRTI在许多疾病中的用途。 患者因此，需要新的NNRTI来克服目前的NNRTI耐药HIV毒株。本研究的目的 是鉴定对耐药病毒有效的新的非核苷类逆转录酶抑制剂。我们之前已经发现了两类 NNRTI、二芳基苯胺（DAAN）和二芳基吡啶胺（DAPA），它们在结构上不同于 批准的二芳基嘧啶（DAPY）型药物依曲韦林和利匹韦林。每一个化学类都可以完全 克服一些流行的NNRTI耐药突变。然而，没有一种对所有流行的 NNRTI耐药HIV-1变体。为了完全克服NNRTI抗性，我们已经确定了关键的结构 每种化学品类别的特征是有效对抗耐药病毒所必需的。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， 将对耐当前NNRTI的病毒有效。为了验证我们的假设并实现我们的目标，我们 我们提出以下两个具体目标。目的一是设计合成新型二芳基苯胺（DAAN） 和二芳基吡啶胺（达帕）衍生物以克服对NNRTI具有抗性的HIV-1变体。这一目标将是 通过设计新的NNRTI来实现，这些NNRTI包括克服耐药性的有利结构特征 选自DAAN/DAPA。目的二是建立新的非核苷类逆转录酶抑制剂的药理学特征 对抗耐药HIV-1。药理学研究旨在建立基础/初始药理学 为未来更全面的药物-靶点相互作用研究和临床药物研究铺平道路 发展实现这一目标将为进一步开发化合物提供必要的信息 临床前药物开发，以减轻NNRTI耐药性。我们的化学合成将得到 传统药物化学和现代分子建模。引导优化将由良好的- 分别建立了针对野生型和NNRTI耐药病毒的初级和二级生物学试验。 该研究小组的独特定位是基于二十多年的抗艾滋病毒研究来开展这项奋进 research.随着已确认的有希望的线索已经在手，再加上建立生物测定的可用性 系统，我们相信我们可以发现和开发新的NNRTI，以克服普遍的NNRTI 抵抗病毒。