D-peptide Inhibitors of HIV-1 Entry

描述(由申请人提供)：抑制艾滋病毒进入是一种很有希望的战略，目前的药物尚未对其进行最佳利用。这项建议旨在开发和表征一类新型的抗蛋白酶D-肽，它与HIV gp41的高度保守的口袋区域结合，并阻止病毒进入。D-肽由镜像D-氨基酸组成，不被天然蛋白酶降解。因此，与传统的L肽抑制剂相比，它们有可能在体内持续更长时间，从而能够以低得多的成本大幅降低和减少剂量。PIE12-三聚体是一种高效的D-肽抑制剂，可广泛抑制所有主要的HIV分支。它的设计采用了新型的“电阻电容器”，这是一种结合能的储备，据预测，这种结合能提供了一种高抗性的遗传屏障。事实上，与上一代D-肽或批准的进入抑制剂Fuzeon相比，PIE12-三聚体出现耐药株的速度要慢得多。这项提议将建立在D-肽和PIE12-三聚体的承诺基础上，通过设计和表征更有效的具有PM效力的膜定位变体。这些D-肽在体内的性质将被检测，以了解它们的免疫原性和代谢命运。HIV最终抵抗PIE12-三聚体和早期D-肽的机制将使用深度测序来表征，以帮助预测其临床用途，并为下一代抑制剂的设计提供信息。新的高通量多肽筛选技术将用于开发耐受PIE12-三聚体耐药突变的下一代D-多肽。这些研究将推动D-肽进入抑制剂作为艾滋病毒预防和治疗药物的使用。了解HIV是如何抵抗这种新型抑制剂的，也将提高我们对耐药机制的理解，并指导设计具有更强大耐药曲线的抑制剂。这些研究还将验证快速模块化D-肽设计策略，该策略可以更广泛地应用于抑制不同生物医学应用的蛋白质-蛋白质相互作用，特别是新出现的传染病。

DESCRIPTION (provided by applicant): Inhibition of HIV entry is a promising strategy that has not yet been optimally exploited by current drugs. This proposal seeks to develop and characterize a novel class of protease-resistant D-peptides that bind to the highly conserved pocket region of HIV gp41 and block viral entry. D-peptides, composed of mirror-image D- amino acids, are not degraded by natural proteases. Therefore, they have the potential to persist in the body for extended periods of time compared to traditional L-peptide inhibitors, enabling dramatically lower and less frequent dosing at a much lower cost. PIE12-trimer is a highly potent D-peptide inhibitor that broadly inhibits all major HIV clades. It was designed with novel "resistance capacitor", a reserve of binding energy that is predicted to provide a high genetic barrier to resistance. Indeed, the emergence of resistant strains is much slower for PIE12-trimer than earlier generation D-peptides or the approved entry inhibitor Fuzeon. This proposal will build on the promise of D-peptides and PIE12-trimer by designing and characterizing even more potent membrane-localized variants with pM potency. The properties of these D-peptides in the body will be examined to understand their immunogenicity and metabolic fate. The mechanism by which HIV ultimately resists PIE12-trimer and earlier generation D-peptides will be characterized using deep sequencing to help predict its clinical utility and inform the design of next-generation inhibitors. Novel high-throughput peptide screening techniques will be used to develop next-generation D-peptides that tolerate PIE12-trimer resistance mutations. These studies will advance D-peptide entry inhibitors for use as HIV preventative and therapeutic agents. Understanding how HIV resists this novel class of inhibitors will also improve our understanding of resistance mechanisms and guide the design of inhibitors with more robust resistance profiles. These studies will also validate a rapid modular D-peptide design strategy that can be applied more broadly to inhibit protein- protein interactions for diverse biomedical applications, particularly emerging infectious diseases.