D-peptide Inhibitors of HIV-1 Entry

HIV-1 进入的 D 肽抑制剂

• 批准号: 8501890
• 负责人: Michael S Kay
• 金额: $ 37.38万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8501890
• 关键词: Address; Affect; Affinity; Alkanes; Amino Acids; Binding; Biological Assay; Cell membrane; Cholesterol; Clinical; Development; Diffusion; Dose; Drug Design; Drug resistance; Emerging Communicable Diseases; Future; Fuzeon; Generations; Genetic; Goals; Grant; HIV; HIV Entry Inhibitors; HIV Envelope Protein gp41; HIV-1; Human; Image; Individual; Kinetics; Measures; Mediating; Membrane; Membrane Microdomains; Mutate; Pathway interactions; Peptide Hydrolases; Peptides; Phage Display; Pharmaceutical Preparations; Resistance; Resistance development; Resistance profile; Route; Screening procedure; Site; Solutions; Techniques; Testing; Therapeutic; Therapeutic Agents; Time; Variant; Viral; Virus; cost; design; fitness; improved; inhibitor/antagonist; insight; microbicide; next generation; novel; pathogen; peptide L; protein protein interaction; resistance mechanism; resistance mutation; resistant strain; scaffold; single molecule

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 mechanism by which HIV ultimately resists PIE12-trimer and earlier generation D-peptides will be characterized using deep sequencing to help predict 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 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.

描述（由申请人提供）：抑制HIV进入是一种有前途的策略，目前的药物尚未最佳利用。该提案旨在开发和表征一类新的蛋白酶抗性D肽，其结合到HIV gp 41的高度保守的口袋区域并阻断病毒进入。由镜像D-氨基酸组成的D-肽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很长一段时间，从而能够以低得多的成本显著降低和减少给药频率。PIE 12-三聚体是一种高效的D-肽抑制剂，广泛抑制所有主要的HIV进化枝。它被设计成具有新型的“电阻电容器”，这是一种结合能储备，预计将提供高遗传抗性屏障。事实上，对于PIE 12-三聚体，耐药菌株的出现比前代D-肽或批准的进入抑制剂Fuzeon慢得多。该提案将通过设计和表征具有pM效力的甚至更有效的膜定位变体来建立D-肽和PIE 12三聚体的前景。HIV最终抵抗PIE 12三聚体和早期D肽的机制将使用深度测序来表征，以帮助预测临床效用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PIE 12三聚体抗性突变的下一代D肽。这些研究将推进D-肽进入抑制剂作为艾滋病毒预防和治疗剂的使用。了解HIV如何抵抗这类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性的抑制剂。这些研究将验证一种快速模块化D肽设计策略，该策略可以更广泛地应用于抑制蛋白质-蛋白质相互作用，用于各种生物医学应用，特别是新兴的传染病。