Boggiano César, Jiang Shibo, Lu Hong, Zhao Qian, Liu Shuwen, Binley James, Blondelle Sylvie E
Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, CA 92121, USA.
Biochem Biophys Res Commun. 2006 Sep 8;347(4):909-15. doi: 10.1016/j.bbrc.2006.06.150. Epub 2006 Jul 5.
Entry of human immunodeficiency virus type 1 (HIV-1) virion into host cells involves three major steps, each being a potential target for the development of entry inhibitors: gp120 binding to CD4, gp120-CD4 complex interacting with a coreceptor, and gp41 refolding to form a six-helix bundle. Using a D-amino acid decapeptide combinatorial library, we identified peptide dC13 as having potent HIV-1 fusion inhibitory activity, and effectively inhibiting infection by several laboratory-adapted and primary HIV-1 strains. While dC13 did not block binding of gp120 to CD4, nor disrupt the gp41 six-helix bundle formation, it effectively blocked the binding of an anti-CXCR4 monoclonal antibody and chemokine SDF-1alpha to CXCR4-expressing cells. However, because R5-using primary viruses were also neutralized, the antiviral activity of dC13 implies additional mode(s) of action. These results suggest that dC13 is a useful HIV-1 coreceptor antagonist for CXCR4 and, due to its biostability and simplicity, may be of value for developing a new class of HIV-1 entry inhibitors.
1型人类免疫缺陷病毒（HIV-1）病毒粒子进入宿主细胞涉及三个主要步骤，每一步都是开发进入抑制剂的潜在靶点：gp120与CD4结合、gp120-CD4复合物与共受体相互作用以及gp41重新折叠形成六螺旋束。利用一个D-氨基酸十肽组合文库，我们鉴定出肽dC13具有强大的HIV-1融合抑制活性，并能有效抑制几种实验室适应株和原代HIV-1毒株的感染。虽然dC13不阻断gp120与CD4的结合，也不破坏gp41六螺旋束的形成，但它能有效阻断抗CXCR4单克隆抗体和趋化因子SDF-1α与表达CXCR4的细胞的结合。然而，由于使用R5的原代病毒也被中和，dC13的抗病毒活性意味着还有其他作用方式。这些结果表明，dC13是一种有用的针对CXCR4的HIV-1共受体拮抗剂，并且由于其生物稳定性和简单性，可能对开发一类新型HIV-1进入抑制剂具有价值。
