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

摘要 HIV/AIDS的抗逆转录病毒疗法(ART)在临床治疗HIV-1感染方面是有效的。非核苷 逆转录酶抑制物(NNRTI)是一类抗逆转录病毒药物，在抗逆转录病毒治疗的成功中起着重要作用 艺术。然而，抗药性病毒的出现限制了NNRTI在许多情况下的用途 病人。因此，需要新的NNRTI来克服目前对NNRTI耐药的艾滋病毒株。这项研究的目的是 是确定对耐药病毒有效的新的NNRTI。我们之前已经发现了两类 NNRTIs、二芳基苯胺(DAANs)和二芳基吡二胺(DAPAs)，它们在结构上不同于 批准的二芳基嘧啶(DAPY)类药物依特拉韦林和利培韦林。每一节化学课都可以完全 克服一些流行的NNRTI耐药突变。然而，没有一种方法对所有流行的 耐NNRTI的HIV-1变种。为了完全克服NNRTI的阻力，我们已经确定了关键的结构性 有效对抗抗药性病毒所需的每一种化学类别的特征。我们 假设可以合成具有对抗药性病毒有效的结构特征的化合物，并且 将对对当前NNRTI具有耐药性的病毒有效。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设计和合成新的二芳基苯胺(DAAN) 和二芳基吡啶胺(DAPA)衍生物，以克服艾滋病毒-1变种对NNRTIs的抗药性。这一目标将是 通过设计新的NNRTI实现，该NNRTI包括克服耐药性的有利结构特征 从DAAN/DAPAS中选择。目标2是建立有效的新NNRTI的药理学概况 对抗抗药性HIV-1。药理学研究的目的是建立基础/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铺平道路 发展。实现这一目标将为进一步发展化合物提供必要的信息 临床前药物开发以减轻NNRTI耐药性。我们的化学合成将由 传统药物化学和现代分子建模。领先的优化将由Well-Well指导 分别建立了对野生型和NNRTI耐药病毒的初级和二级生物学测试。 基于二十多年的抗艾滋病毒经验，该研究团队处于独特的地位来进行这项工作 研究。已经证实有希望的线索，再加上已建立的生物检测的可用性 我们相信，我们能够发现和开发新的NNRTI，以克服流行的NNRTI 抗药性病毒。

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.