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 进入是一种很有前途的策略，但目前的药物尚未最佳利用。该提案旨在开发和表征一类新型抗蛋白酶 D 肽，该肽可与 HIV gp41 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，不会被天然蛋白酶降解。因此，与传统的 L 肽抑制剂相比，它们有可能在体内持续较长时间，从而以更低的成本实现显着更低和更少的给药频率。 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。它采用新颖的“电阻电容器”设计，这是一种结合能储备，预计将提供高遗传抵抗力屏障。事实上，PIE12-三聚体的耐药菌株的出现比上一代 D-肽或已批准的进入抑制剂 Fuzeon 慢得多。该提案将建立在 D 肽和 PIE12 三聚体的基础上，通过设计和表征具有 pM 效力的更有效的膜定位变体。 HIV 最终抵抗 PIE12-三聚体和早期 D 肽的机制将使用深度测序进行表征，以帮助预测临床效用并为下一代抑制剂的设计提供信息。新型高通量肽筛选技术将用于开发能够耐受 PIE12 三聚体抗性突变的下一代 D 肽。这些研究将推动 D 肽进入抑制剂用作 HIV 预防和治疗药物。了解艾滋病毒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多种生物医学应用中的蛋白质-蛋白质相互作用，特别是新出现的传染病。