Adding an Artificial TailAnchor to a Peptide-Based HIV-1 Fusion Inhibitor for Improvement of Its Potency and Resistance Profile

作者：Su, Shan; Ma, Zhenxuan; Hua, Chen; Li, Weihua; Lu, Lu^*; Jiang, Shibo^*

来源：Molecules, 2017, 22(11): 1996.

DOI：10.3390/molecules22111996

• HIV
• gp41
• fusion inhibitor
• six-helix bundle
• peptide

Peptides derived from the C-terminal heptad repeat (CHR) of human immunodeficiency virus type 1 (HIV-1) envelope protein transmembrane subunit gp41, such as T20 (enfuvirtide), can bind to the N-terminal heptad repeat (NHR) of gp41 and block six-helix bundle (6-HB) formation, thus inhibiting HIV-1 fusion with the target cell. However, clinical application of T20 is limited because of its low potency and genetic barrier to resistance. HP23, the shortest CHR peptide, exhibits better anti-HIV-1 activity than T20, but the HIV-1 strains with E49K mutations in gp41 will become resistant to it. Here, we modified HP23 by extending its C-terminal sequence using six amino acid residues (E6) and adding IDL (Ile-Asp-Leu) to the C-terminus of E6, which is expected to bind to the shallow pocket in the gp41 NHR N-terminal region. The newly designed peptide, designated HP23-E6-IDL, was about 2- to 16-fold more potent than HP23 against a broad spectrum of HIV-1 strains and more than 12-fold more effective against HIV-1 mutants resistant to HP23. These findings suggest that addition of an anchor-tail to the C-terminus of a CHR peptide will allow binding with the pocket in the gp41 NHR that may increase the peptide's antiviral efficacy and its genetic barrier to resistance.

• 出版日期2017-11
• 单位复旦大学; 上海市计划生育科学研究所