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基本组成部分可防止病毒进入和感染。我们的抑制肽由D-氨基酸(D-肽)组成，D-氨基酸对天然蛋白酶具有抵抗力，预计比传统的L肽抑制剂在体内存活的时间要长得多。我们将使用基于结构的蛋白质设计和噬菌体展示筛选相结合的方法，在HIV进入试验中寻找与N-三聚体具有高亲和力和强大抗病毒效力的D-肽。我们还建议使与gp41结合的多聚体D-肽具有更强的亲和力和抗病毒效力。我们将确定这些D-肽与它们的N-三聚体靶标形成的复合体的高分辨结构，以确定它们的效力来源，并指导改进的D-肽的设计。有效的D-肽进入抑制剂作为抗逆转录病毒鸡尾酒的额外治疗成分和预防性杀微生物剂都是有用的。这些研究也可能对开发其他D-肽病毒进入抑制剂和提高我们对D-肽设计的总体知识具有广泛的适用性。 公共卫生相关性：开发有效的抗蛋白酶D-肽抑制艾滋病毒进入将有助于治疗感染患者(治疗剂)，以及预防新的感染(预防性试剂)。更好地理解D-肽的设计将促进这些耐寒多肽在科学研究和医学上的广泛应用的未来发展。

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.