Development of Novel Scaffolds as Tools for Allosteric HIV-1 Integrase Inhibition

摘要 HIV-1整合酶(IN)是病毒生命周期中开发新疗法的关键靶点。 尽管FDA批准的活性部位抑制剂如Raltegravir的成功开发， Elvitegravir和dolutegravir对这些药物的耐药性威胁到它们的长期用途。变构 结合在IN的LEDGF/p75位点的IN抑制剂代表了一种替代策略 开发不会具有相同耐药性的化合物。这些变构 最近发现，抑制剂通过促进异常信号通路来影响IN的活性 多聚化，这一过程仍未得到很好的理解。据信，绑定到 IN的CCD二聚体界面内的LEDGF/p75口袋诱导另一个IN的招募 然后能够结合在这个位点上的蛋白质，导致形成一个不活跃的更高顺序 齐聚物。目前的提案重点是开发旨在探索的化合物 In CCD二聚体/CTD接口，以努力更有效地“催化”这一过程，导致 IN的抑制作用。这项提议的一个关键组成部分也是开发一种全新的 能够结合到LEDGF/p75口袋上的支架，预计会显示出独特的阻力 与先前合成的变构抑制剂进行比较。

Abstract HIV-1 integrase (IN) is a key target in the viral life cycle for the development of new therapeutics. Despite the successful development of FDA approved active site inhibitors like raltegravir, elvitegravir, and dolutegravir, resistance to these agents threatens their long-term utility. Allosteric IN inhibitors that bind at the LEDGF/p75 site of IN represent an alternative strategy for the development of compounds that will not share the same resistance profile. These allosteric inhibitors have recently been shown to affect IN activity through promotion of aberrant multimerization, a process that is still not well understood. It is believed that binding to the LEDGF/p75 pocket within the CCD dimer interface of IN induces the recruitment of another IN protein that then is able to bind at this site, resulting in the formation of an inactive higher order oligomer. The current proposal is focused on the development of compounds designed to probe the IN CCD dimer/CTD interface in an effort to more efficiently “catalyze” this process, leading to the inhibition of IN. A key component of this proposal is also the development of a completely new scaffold capable of binding to the LEDGF/p75 pocket and predicted to show a unique resistance profile compared to previously synthesized allosteric inhibitors.