D-peptide Inhibitors of HIV-1 Entry

描述（由申请人提供）：我们建议开发针对 HIV gp41 高度保守的 N-三聚体口袋区域的新型 HIV 进入抑制剂。抑制艾滋病毒融合机制的这一重要组成部分可以防止病毒进入和感染的建立。我们的抑制肽由 D-氨基酸（D-肽）组成，可抵抗天然蛋白酶，预计在体内的存活时间比传统的 L-肽抑制剂要长得多。我们将结合使用基于结构的蛋白质设计和噬菌体展示筛选来鉴定对 N-三聚体具有高亲和力且在 HIV 进入检测中具有强抗病毒效力的 D-肽。我们还建议制备与 gp41 结合的多聚体 D 肽，具有更高的亲和力和抗病毒效力。我们将确定这些 D-肽与其 N-三聚体靶标复合物的高分辨率结构，以确定其效力的来源并指导改进的 D-肽的设计。有效的D-肽进入抑制剂既可用作抗逆转录病毒混合物的附加治疗成分，也可用于预防性杀微生物剂。这些研究也可能对其他 D 肽病毒进入抑制剂的开发以及提高我们对 D 肽设计的总体了解具有广泛的适用性。 公共健康相关性：开发有效的 HIV 进入的抗蛋白酶 D 肽抑制剂将有助于治疗感染患者（治疗剂）以及预防新感染（预防剂）。对 D 肽设计的更好理解将刺激这些耐寒肽在科学研究和医学领域的多种应用的未来发展。

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.