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

具有新颖作用机制的小分子 HIV-1 进入抑制剂

基本信息

批准号：
9884724
负责人：
Chin-Ho Chen
金额：
$ 41.83万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9884724
关键词：
AIDS therapy Animal Model Anti-HIV Agents Anti-Inflammatory Agents Anti-Retroviral Agents Antibodies Antiviral Agents Binding Biological Clinical Trials Disease Drug Binding Site Drug Design Drug Kinetics Drug resistance Drug toxicity Effectiveness Evaluation Exhibits Future Goals HIV HIV Entry Inhibitors HIV Envelope Protein gp120 HIV-1 Individual Infection Inflammation Inflammatory Lead Life Cycle Stages Mediating Membrane Fusion Molecular Mechanisms of Action Natural Products Pathogenesis Pharmacology Phase Photoaffinity Labels Plants Property Proteins Research Research Project Grants Structure Structure-Activity Relationship Testing Toxic effect Viral Virus Virus Replication Work analog animal efficacy antiretroviral therapy base design drug candidate drug development drug discovery drug resistant virus efficacy study functional group improved in silico inhibitor/antagonist lead optimization neutralizing antibody novel novel therapeutics preclinical development scaffold small molecule synergism

项目摘要

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.

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，但这种方法的效果并不明显