Importance of structure-based studies for the design of a novel HIV-1 inhibitor peptide

María J. Gomara,Juan J. Perez,Andreas Meyerhans,Isabel Haro,Patricia Gomez-Gutierrez,Javier P. Martinez,Carolina Herrera,Paul Ziprin,Yolanda Perez

doi:10.1038/s41598-020-71404-0

Abstract

Based on the structure of an HIV-1 entry inhibitor peptide two stapled- and a retro-enantio peptides have been designed to provide novel prevention interventions against HIV transmission. The three peptides show greater inhibitory potencies in cellular and mucosal tissue pre-clinical models than the parent sequence and the retro-enantio shows a strengthened proteolytic stability. Since HIV-1 fusion inhibitor peptides need to be embedded in the membrane to properly interact with their viral target, the structural features were determined by NMR spectroscopy in micelles and solved by using restrained molecular dynamics calculations. Both parent and retro-enantio peptides demonstrate a topology compatible with a shared helix–turn–helix conformation and assemble similarly in the membrane maintaining the active conformation needed for its interaction with the viral target site. This study represents a straightforward approach to design new targeted peptides as HIV-1 fusion inhibitors and lead us to define a retro-enantio peptide as a good candidate for pre-exposure prophylaxis against HIV-1.

Highlights

The therapeutic utility of synthetic peptides as Human Immunodeficiency Virus (HIV) fusion inhibitors is largely limited due to their natural proteogenic structure, which is recognized and degraded by proteolytic enzymes
E1P47 derives from the region 139–156 of the E1 protein of the Human Pegivirus which can be considered as commensal of humans since infections provide a beneficial effect on survival in HIV-1 positive subjects[24]
Several experimental data demonstrated that E1P47 can be considered as an inhibitor of HIV-1 Env fusion; (1) the peptide inhibited HIV-1 Env mediated cell fusion[23]; (2) the peptide was not able to inhibit an amphotropic vesicular stomatitis virus (VSV) Env pseudotyped on an HIV-1 core[23] (3) peptide–peptide titrations and diffusion Nuclear Magnetic Resonance (NMR) spectroscopy demonstrated the specific interaction of E1P47 peptide with its viral target site, the HIV-1 fusion p eptide[25]

Summary

Introduction

The therapeutic utility of synthetic peptides as Human Immunodeficiency Virus (HIV) fusion inhibitors is largely limited due to their natural proteogenic structure, which is recognized and degraded by proteolytic enzymes. Retro-D peptides, which display a similar topological arrangement as their parent peptides, offer the advantage of overcoming immunological problems when they are used as therapeutic a gents[8] Despite these advantages, a limited number of studies have addressed the therapeutic usefulness of d-peptide structures as HIV-1 fusion inhibitors[9]. To envisage the in vitro half-life of the peptides, their proteolytic stability in human serum was analysed Their anti-viral activity was tested in cells and in an ex vivo human mucosal tissue models to gain more knowledge about possible therapeutic application of the synthesized peptides. Taking into account that fusion inhibitor peptides interfering with the N-terminal region of gp4121 need to be embedded into the membrane in order to properly interact with their viral target[22], we studied the peptide assembly on the membrane as well as the recognition of its viral target on a membrane mimetic environment

Methods

Results

Conclusion