D-peptide Inhibitors of HIV-1 Entry

描述（由申请人提供）：我们建议开发靶向HIV gp 41高度保守的N-三聚体口袋区域的新型HIV进入抑制剂。抑制HIV融合机制的这一基本成分可以防止病毒进入并建立感染。我们的抑制肽由D-氨基酸（D-肽）组成，其对天然蛋白酶具有抗性，预计在体内的存活时间比传统的L-肽抑制剂长得多。我们将使用基于结构的蛋白质设计和噬菌体展示筛选的组合来鉴定对N-三聚体具有高亲和力的D-肽和HIV进入测定中的强抗病毒效力。我们还提出，使多聚体D-肽结合到gp 41具有更大的亲和力和抗病毒的效力。我们将确定这些D-肽与它们的N-三聚体靶标复合的高分辨率结构，以确定它们效力的来源并指导改进的D-肽的设计。有效的D-肽进入抑制剂将可用作抗逆转录病毒鸡尾酒的额外治疗组分和预防性杀微生物剂用途。这些研究也可能具有广泛的适用性，为其他D-肽病毒进入抑制剂的发展和提高我们的知识D-肽的设计一般。 公共卫生相关性：HIV进入的有效蛋白酶抗性D肽抑制剂的开发将可用于治疗感染患者（治疗剂）以及预防新感染（预防剂）。更好地理解D-肽的设计将促进这些哈代肽在科学研究和医学中的各种应用的未来发展。

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.