D-peptide Inhibitors of HIV-1 Entry

描述（由申请人提供）：抑制HIV进入是一种很有前途的策略，目前的药物尚未充分利用。这一提议旨在开发和表征一类新的蛋白酶抗性d肽，这些d肽结合到HIV gp41的高度保守的口袋区并阻止病毒进入。D-肽是由镜像D-氨基酸组成的，不能被天然蛋白酶降解。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的时间，从而以更低的成本大大降低和减少剂量。PIE12-trimer是一种高效的d肽抑制剂，广泛抑制所有主要的HIV分支。它设计了一种新型的“电阻电容”，一种结合能的储备，预计将提供高的遗传屏障。事实上，PIE12-trimer的耐药菌株的出现比早期的d肽或批准的进入抑制剂Fuzeon要慢得多。该提案将通过设计和表征具有pM效力的更有效的膜定位变体，以d肽和pie12 -三聚体的前景为基础。这些d肽在体内的性质将被检查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 -肽的机制将通过深度测序来表征，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。新的高通量肽筛选技术将用于开发耐受pie12 -三聚体抗性突变的下一代d肽。这些研究将促进d肽进入抑制剂作为HIV预防和治疗药物的使用。了解HIV如何抵抗这种新型抑制剂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谱的抑制剂。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多种生物医学应用，特别是新出现的传染病，以抑制蛋白质-蛋白质相互作用。

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.