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

Shan Su,Shibo Jiang,Zhenxuan Ma,Lu Lu,Weihua Li,Chen Hua

doi:10.3390/molecules22111996

Abstract

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.

Highlights

Human immunodeficiency virus (HIV) is the causative pathogen of acquired immune deficiency syndrome (AIDS)
HP23, the shortest C-terminal heptad repeat (CHR) peptide (23 aa), has relatively potent anti-human immunodeficiency virus type 1 (HIV-1) activity, mainly because its N-terminal portion contains the EMT-anchor structure and pocket-binding sequence, which can strongly bind to the deep hydrophobic pocket (C-pocket) in the C-terminal groove of the N-terminal heptad repeat (NHR)-trimer (Figure 1b,c)
HIV-1 with E49K mutation in the gp41 NHR became resistant to HP23 [24]

Summary

Introduction

Human immunodeficiency virus (HIV) is the causative pathogen of acquired immune deficiency syndrome (AIDS). 35 individual anti-HIV drugs and five combination formulas have been approved for clinical use By the U.S Food and Drug Administration (FDA). United Nations Programme in HIV and AIDS (UNAIDS), only 82% of HIV/AIDS patients on treatment had suppressed viral loads at the time of the survey Documents/2017/20170720_Global_AIDS_update_2017), meaning that about 3.5 million HIV-infected patients receiving antiviral treatment showed no control of their disease progress. One major reason is that HIV-1 rapidly mutates during treatment and quickly acquires resistance to the anti-HIV drugs used. Most anti-HIV drugs have been reported to induce drug-resistant HIV-1 strains within several weeks to several years after drug treatment [1,2,3]. In a 2016 Mexican survey, about 14.4%

Methods

Results

Conclusion