Structure-Guided Design of Peptide Inhibitors Targeting Class I Viral Fusion Proteins

TL;DR

This paper reviews how to design peptides that block viruses from entering cells by targeting their fusion proteins, using structural insights to improve effectiveness.

Contribution

The paper provides a comprehensive overview of structure-guided strategies for optimizing peptide inhibitors targeting viral fusion proteins.

Findings

Peptide inhibitors mimicking heptad repeat motifs are effective in blocking viral fusion.

Strategies like α-helical stabilization and hydrocarbon stapling improve peptide potency and stability.

These approaches have led to the development of broad-spectrum antiviral peptides.

Abstract

Viral fusion proteins are indispensable mediators of viral entry that orchestrate the fusion of viral and host membranes, making them primary targets for antiviral interventions. Class I fusion proteins, displayed on the surface of enveloped viruses (such as HIV-1, RSV, SARS-CoV-2, Nipah, influenza, and Ebola viruses), share conserved structural features, including the fusion peptide or loop and heptad repeat regions. These elements are essential for the formation of the post-fusion six-helix bundle during membrane fusion. Peptide inhibitors that mimic heptad repeat motifs have consequently emerged as an effective strategy for blocking the fusion process. This review summarizes design strategies for such inhibitors and highlights how sequence and structural insights have enabled their optimization via α-helical stabilization, hydrocarbon stapling, lactam bridges, lipid conjugation, macrocyclization, and multivalency. Using representative examples across major viral systems, this review illustrates how these strategies have led to the development of potent, stable, and even broad-spectrum antiviral peptides. This review provides insights to guide the rational design of next-generation peptide-based fusion inhibitors targeting viral membrane fusion.

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