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HIV融合机制的这一重要组成部分可防止病毒进入并建立感染。我们的抑制肽是由d -氨基酸（d -肽）组成的，它对天然蛋白酶具有抗性，并且预计比传统的l -肽抑制剂在体内存活的时间更长。我们将结合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和强抗病毒效力的d肽。我们还建议制造与gp41结合的多聚d肽，具有更高的亲和力和抗病毒效力。我们将确定这些d肽及其N-三聚体靶复合物的高分辨率结构，以确定其效力的来源，并指导改进d肽的设计。有效的d肽进入抑制剂既可作为抗逆转录病毒鸡尾酒的额外治疗成分，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和提高我们对d肽设计的总体认识具有广泛的适用性。

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.