Anti-HIV-1 Peptide Derivatives Based on the HIV-1 Co-receptor CXCR4

作者：Hashimoto Chie; Nomura Wataru; Narumi Tetsuo; Fujino Masayuki; Tsutsumi Hiroshi; Haseyama Masaki; Yamamoto Naoki; Murakami Tsutomu; Tamamura Hirokazu^*

来源：ChemMedChem, 2013, 8(10): 1668-1672.

DOI：10.1002/cmdc.201300289

• antiviral agents
• CXCR4
• HIV-1 entry inhibitors
• extracellular domains
• peptides

The human immunodeficiency virus type1 (HIV-1) uses CD4 and the co-receptor CCR5 or CXCR4 in the process of cell entry. The negatively charged extracellular domains of CXCR4 (CXCR4-ED) interact with positive charges on the V3 loop of gp120, facilitating binding via electrostatic interactions. The presence of highly conserved positively charged residues in the V3 loop suggests that CXCR4-ED-derived inhibitors might be broadly effective inhibitors. Synthetic peptide derivatives were evaluated for anti-HIV-1 activity. The 39-mer extracellular N-terminal region (NT) was divided into three fragments with 10-mer overlapping sites (N1-N3), and these linear peptides were synthesized. Peptide N1 contains Met1-Asp20 and shows significant anti-HIV-1 activity. Extracellular loops1 and 2 (ECL1 and 2) were mimicked by cyclic peptides C1 and C2, which were synthesized by chemoselective cyclization. Cyclic peptides C1 and C2 show higher anti-HIV-1 activity than their linear peptide counterparts, L1 and L2. The cytotoxicities of C1 and C2 are lower than those of L1 and L2. These results indicate that Met1-Asp20 segments of the NT and cyclic peptides of ECL1 and ECL2 are potent anti-HIV-1 drug candidates.

• 出版日期2013-10