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阳性个体的病毒复制， 病毒被抑制而不是被真正根除。此外，与长期- 长期ART仍然是有效AIDS治疗一个重大挑战。因此，需要开发新的 作为开发新型抗肿瘤药物的一步， 在HIV药物中，我们已经鉴定了一类喹嗪类药物，包括苦豆碱，其通过以下方式在1-5 μ M时抑制HIV： 阻止病毒进入Aloperine已被证明具有抗炎特性，这可能是潜在的 有益于缓解与HIV-1感染相关的免疫发病机制。我们的初步结构 优化已经产生抗HIV-1活性增加约15倍的苦豆碱衍生物。我们 作用机制研究表明，gp 120的V1/V2环，这是几个广泛而有效的靶点， 中和抗体是目前的苦豆碱铅衍生物的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HIV喹嗪啶： 合理的药物设计，成为具有新作用机制的抗HIV-1候选药物。这个目标 研究项目是提高苦豆碱衍生物的抗HIV效力，并测定其药理学活性 概况，如作用机制和抗HIV活性的广度，这对进一步的药物治疗至关重要。 发展为了检验这一假设并实现我们的目标，我们将实施以下具体目标： 鉴定有前景的抗HIV进入抑制剂：1）阐明抗HIV进入抑制剂的分子作用机制， 喹里嗪类化合物的HIV-1进入活性; 2）通过先导化合物优化鉴定有效的喹里嗪衍生物; 3） 建立苦豆碱衍生物的抗HIV-1特性。Aloperine（MW=232）是一种天然产物， 几种常见的植物物种，可以通过全合成得到。Aloperine已被证明具有最佳的 PK特征，并在炎性疾病的动物模型中有效。因此，这是一个有吸引力的打击铅 优化.这种具有双重作用模式的化合物可以成为ART的有用补充，并且具有 可能减少与持续HIV-1感染相关的炎症。我们计划在一九九九年完成这项研究。 三年达到以下里程碑：a）获得具有低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，和c）鉴定苦豆碱 显示交叉进化枝抗HIV-1活性和最佳药代动力学特征的衍生物。完成 这项工作的建议将产生非常有前途的抗艾滋病毒1剂，并为他们的进一步临床前的关键 开发，包括动物功效研究和其抗炎活性的优化。

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.