D-peptide Inhibitors of HIV-1 Entry

HIV-1 进入的 D 肽抑制剂

• 批准号: 7926658
• 负责人: Michael S Kay
• 金额: $ 8.39万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-22 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7926658
• 关键词: Affinity; Algorithms; Amino Acids; Anti-Retroviral Agents; Antiviral Agents; Avidity; Binding; Biological Assay; Biosensor; Cell Line; Clinical; Clinical Trials; Clinical effectiveness; Complex; Crosslinker; Development; Drug resistance; Engineering; Epidemic; Equilibrium; Future; Fuzeon; General Population; Goals; HIV; HIV Entry Inhibitors; HIV Envelope Protein gp41; HIV-1; Human; Image; Infection; Kinetics; Knowledge; Length; Light; Local Microbicides; Measures; Mediating; Medicine; Membrane Fusion; National Institute of Allergy and Infectious Disease; Pathway interactions; Patients; Peptide Hydrolases; Peptides; Peripheral Blood Mononuclear Cell; Phage Display; Prevention; Property; Proteins; Reporting; Research; Resistance; Resolution; Screening procedure; Series; Source; Structure; T-20; Therapeutic; Therapeutic Agents; Time; Viral; Virus; animal efficacy; base; cost; design; dimer; fitness; improved; inhibitor/antagonist; large scale production; microbicide; mutant; novel; peptide L; peptide structure; pre-clinical; preclinical evaluation; prevent; prophylactic; public health relevance; resistance mechanism; resistance mutation

DESCRIPTION (provided by applicant): We propose to develop novel inhibitors of HIV entry that target the highly conserved N-trimer pocket region of HIV gp41. Inhibition of this essential component of HIV's fusion machinery prevents viral entry and the establishment of infection. Our inhibitory peptides are composed of D-amino acids (D-peptides), which are resistant to natural proteases and are predicted to survive in the body for much longer periods of time than traditional L-peptide inhibitors. We will use a combination of structure-based protein design and phage display screening to identify D-peptides with high affinity for the N-trimer and strong antiviral potency in HIV entry assays. We also propose to make multimeric D-peptides that bind to gp41 with greater affinity and antiviral potency. We will determine the high-resolution structures of these D-peptides in complex with their N- trimer target to determine the sources of their potency and to guide the design of improved D-peptides. Potent D-peptide entry inhibitors would be useful both as an additional therapeutic component of an antiretroviral cocktail and for prophylactic microbicide use. These studies will also likely have broad applicability for the development of other D-peptide viral entry inhibitors and for improving our knowledge of D-peptide design in general. PUBLIC HEALTH RELEVANCE: The development of potent protease-resistant D-peptide inhibitors of HIV entry will be useful for the treatment of infected patients (therapeutic agent), as well as the prevention of new infections (prophylactic agent). A better understanding of D-peptide design will stimulate future development of these hardy peptides for diverse applications in scientific research and medicine.

描述（由申请人提供）：我们建议开发针对HIV GP41高度保守的N-Trimer口袋区域的HIV进入的新型抑制剂。抑制艾滋病毒融合机械的这一基本组成部分可防止病毒进入和建立感染。我们的抑制性肽由D-氨基酸（D肽）组成，它们对天然蛋白酶具有抗性，并且预测在体内生存的时间比传统的L肽抑制剂更长。我们将使用基于结构的蛋白质设计和噬菌体显示筛选的组合来鉴定对HIV入学分析中N-三分球和强抗病毒效力具有高亲和力的D肽。我们还建议使具有更大亲和力和抗病毒效力的GP41结合的多聚体D肽。我们将确定这些D肽及其N型靶标的高分辨率结构，以确定其效力的来源并指导改进的D肽的设计。有效的D肽进入抑制剂将作为抗逆转录病毒鸡尾酒的附加治疗成分和用于预防性杀菌剂的使用。这些研究可能还可能对开发其他D肽病毒入口抑制剂的开发以及提高我们对D肽设计的知识具有广泛的适用性。 公共卫生相关性：抗HIV进入的有效蛋白酶D肽抑制剂的发展对于治疗感染患者（治疗剂）以及预防新感染（预防剂）将很有用。对D肽设计的更好理解将刺激这些强硬肽在科学研究和医学中的不同应用中的未来发展。