The Role of Structural Flexibility in Hydrocarbon-Stapled Peptides Designed to Block Viral Infection via Human ACE2 Mimicry

Sicheng Jiang, Yu Tian, Vlad Nicolaescu, Aslan Mansurov, Glenn Randall, Matthew V Tirrell, James L LaBelle

Research output: Contribution to journalArticlepeer-review

Abstract

The COVID-19 pandemic drove a uniquely fervent pursuit to explore the potential of peptide, antibody, protein, and small-molecule-based antiviral agents against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The interaction between the SARS-CoV2 spike protein with the angiotensin-converting enzyme 2 (ACE2) receptor that mediates viral cell entry was a particularly interesting target given its well-described protein–protein interaction (PPI). This PPI is mediated by an α-helical portion of ACE2 binding to the receptor binding domain (RBD) of the spike protein and thought to be susceptible to blockade through molecular mimicry. Small numbers of hydrocarbon-stapled synthetic peptides designed to disrupt or block this interaction were tested individually and were found to have variable efficacy despite having related or overlapping sequences and similarly increased α-helicity. Reasons for these differences are unclear and reported preclinical successes have been limited. This study sought to better understand reasons for these differences through evaluation of a comprehensive collection of hydrocarbon-stapled peptides, designed based on four distinct principles: stapling position, number of staples, amino acid sequence, and primary sequence length. Surprisingly, we observed that the helicity and amino acid sequence iterations of hydrocarbon-stapled peptides did not correlate with their bioactivity. Our results highlight the importance of iterative and combinatorial testing of these compounds to determine a configuration that best mimics natural binding and allows for chain flexibility while sacrificing structural helicity.

Original languageEnglish (US)
JournalPeptide Science
DOIs
StateAccepted/In press - 2024

Bibliographical note

Publisher Copyright:
© 2024 The Author(s). Peptide Science published by Wiley Periodicals LLC.

Keywords

  • SARS-CoV-2
  • protein–protein interaction
  • rational design
  • stapled peptides

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