Design of Artificial C-Peptides as Potential Anti-HIV-1 Inhibitors Based on 6-HB Formation Mechanism

Title:Design of Artificial C-Peptides as Potential Anti-HIV-1 Inhibitors Based on 6-HB Formation Mechanism

Volume: 31 Issue: 6

Author(s): Hui Luo, Yan Zhao, Yuheng Ma, Guodong Liang*, Lu Ga*Zhao Meng*

Affiliation:

• Key Laboratory for Candidate Drug Design and Screening Based on Chemical Biology, College of Pharmacy, Inner Mongolia Medical University, Hohhot, P.R. China

• Key Laboratory for Candidate Drug Design and Screening Based on Chemical Biology, College of Pharmacy, Inner Mongolia Medical University, Hohhot, P.R. China

• State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, P.R. China

Abstract:

Background: The six-helix bundle (6-HB) is a core structure formed during the membrane fusion process of viruses with the Class I envelope proteins. Peptide inhibitors, including the marketed Enfuvirtide, blocking the membrane fusion to exert inhibitory activity were designed based on the heptads repeat interactions in 6-HB. However, the drawbacks of Enfuvirtide, such as drug resistance and short half-life in vivo, have been confirmed in clinical applications. Therefore, novel design strategies are pivotal in the development of next-generation peptide-based fusion inhibitors.

Objective: The de novo design of α-helical peptides against MERS-CoV and IAVs has successfully expedited the development of fusion inhibitors. The reported sequences were completely nonhomologous with natural peptides, which can provide some inspirations for the antiviral design against other pathogenic viruses with class I fusion proteins. Here, we design a series of artificial C-peptides based on the similar mechanism of 6-HB formation and general rules of heptads repeat interaction.

Methods: The inhibitory activity of peptides against HIV-1 was assessed by HIV-1 Env-mediated cell-cell fusion assays. Interaction between artificial C-peptides and target peptides was evaluated by circular dichroism, polyacrylamide gel electrophoresis, size-exclusion chromatography, and sedimentation velocity analysis. Molecular docking studies were performed by using Schrödinger molecular modelling software.

Results: The best-performing artificial C-peptide, 1SR, was highly active against HIV-1 env-mediated cell-cell fusion. 1SR binds to the gp41 NHR region, assembling polymer to prevent endogenous 6-HB formation.

Conclusion: We have found an artificial C-lipopeptide lead compound with inhibitory activity against HIV-1. Also, this paper enriched both N- and C-teminal heptads repeat interaction rules in 6-HB and provided an effective idea for next-generation peptide-based fusion inhibitors against HIV-1.

Cite this article as:

Luo Hui, Zhao Yan, Ma Yuheng, Liang Guodong*, Ga Lu*, Meng Zhao*, Design of Artificial C-Peptides as Potential Anti-HIV-1 Inhibitors Based on 6-HB Formation Mechanism, Protein & Peptide Letters 2024; 31 (6) . https://dx.doi.org/10.2174/0109298665312274240530060233

DOI https://dx.doi.org/10.2174/0109298665312274240530060233	Print ISSN 0929-8665
Publisher Name Bentham Science Publisher	Online ISSN 1875-5305