Small Molecule HIV-1 Entry Inhibitor with Novel Mechanisms of Action

虽然抗逆转录病毒疗法(ART)可以成功地控制HIV-1阳性患者的病毒复制，但 病毒被抑制，而不是真正被根除。此外，与长期接触的毒性和抗药性 长期抗逆转录病毒治疗仍然是有效的艾滋病治疗的一个重大挑战。因此，有必要开发新的 以新的作用机制改善目前的抗逆转录病毒治疗。作为开发新型反病毒药物的一步 我们已经确定了一类喹诺利定类药物，包括alopine，它们通过以下方式在1-5um抑制HIV 阻止病毒入侵。苦参碱已被证明具有抗炎特性，这可能是潜在的 有利于缓解与HIV-1感染相关的免疫病理机制。我们的初步结构 优化得到的苦豆子碱衍生物具有大约15倍的抗HIV-1活性。我们的 作用机制研究表明，gp120的V1/V2环是几个广泛而有效的靶点 中和抗体，是当前先导苦豆碱衍生物抗进入活性的关键决定因素。 基于这些有希望的结果，我们假设可以通过以下途径获得有效的抗艾滋病毒药物 合理的药物设计，成为抗HIV-1药物具有新颖作用机制的候选药物。这样做的目的是 研究项目是提高苦豆子碱衍生物的抗HIV效力并测定其药理作用 概况，如作用机制和抗艾滋病毒活动的广度，这对进一步的药物是必不可少的 发展。为了验证这一假设并实现我们的目标，我们将实现以下具体目标 寻找有希望的抗HIV进入抑制剂：1)阐明抗HIV进入抑制剂的分子作用机制 喹诺利定类化合物的HIV-1进入活性；2)通过先导化合物优化来鉴定有效的喹诺利定衍生物；3) 建立苦豆碱衍生物的抗HIV-1谱。苦豆碱(Mw=232)是一种天然产品，在 几种常见的植物，可通过全合成获得。已有研究表明，苦杏仁碱具有最佳的 PK谱，并在炎症性疾病的动物模型中有效。因此，这对铅来说是一个有吸引力的打击。 优化。这种具有双重作用模式的化合物可能会成为对ART的有益补充，并具有 有可能减少与持续的艾滋病毒-1感染相关的炎症。我们计划在#年完成研究。 三年以达到以下里程碑：a)获得低NM效力的苦豆碱衍生物，b) 阐明这些化合物如何抑制HIV-1进入的新机制，以及c)识别苦杏仁碱 表现出交叉分支的抗HIV-1活性和最佳药代动力学曲线的衍生物。完成 这项提案中的工作将产生非常有希望的抗HIV1药物，并对其进一步的临床前至关重要。 发展包括动物功效研究和抗炎活性的优化。

While anti-retroviral therapy (ART) can successfully control virus replication in HIV-1-positive individuals, the virus is suppressed rather than truly eradicated. Furthermore, toxicity and drug resistance associated with long- term ART remain a significant challenge for effective AIDS therapy. Thus, there is a need to develop new therapeutics with novel mechanisms of action to improve current ART. As a step toward developing novel anti- HIV agents, we have identified a class of quinolizidines, including aloperine, which inhibit HIV at 1-5 uM by blocking viral entry. Aloperine has been shown to exhibit anti-inflammatory properties, which could potentially be beneficial for relieving immunopathogenesis associated with HIV-1 infection. Our preliminary structural optimization has yielded aloperine derivatives with approximately 15-fold increase in anti-HIV-1 activity. Our mechanism of action study reveals that the V1/V2 loop of gp120, which is the target of several broad and potent neutralizing antibodies, is a critical determinant of the anti-entry activity of a current lead aloperine derivative. Based on these promising results, we hypothesize that potent anti-HIV quinolizidines can be obtained through rational drug design and become anti-HIV-1 drug candidates with novel mechanisms of action. The goal of this research project is to improve the anti-HIV potency of aloperine derivatives and determine their pharmacological profiles, such as mechanism of action and the breadth of anti-HIV activity, which are essential for further drug development. The following Specific Aims will be carried out to test this hypothesis and achieve our goal in identifying promising anti-HIV entry inhibitors: 1) to elucidate the molecular mechanisms of action of the anti- HIV-1 entry activity of quinolizidines; 2) to identify potent quinolizidine derivatives through lead optimization; 3) to establish the anti-HIV-1 profiles of aloperine derivatives. Aloperine (MW=232) is a natural product found in several common plant species and can be obtained by total synthesis. Aloperine has been shown to have optimal PK profiles and to be effective in animal models of inflammatory diseases. Thus, it is an attractive hit for lead optimization. Such compounds with the dual modes of action may become a useful addition to ART, and have potential to reduce inflammation associated with persistent HIV-1 infection. We plan to complete the study in three years to reach the following milestones: a) obtaining aloperine derivatives with low nM potency, b) elucidating a novel mechanism of how these compounds inhibit HIV-1 entry, and c) identifying aloperine derivatives that exhibiting cross clade anti-HIV-1 activity and optimal pharmacokinetic profiles. Completion of the work in this proposal will yield highly promising anti-HIV1 agents and is critical for their further preclinical development including animal efficacy studies and optimization of their anti-inflammatory activity.