Issue 2, 2024

Helix-based screening with structure prediction using artificial intelligence has potential for the rapid development of peptide inhibitors targeting class I viral fusion

Abstract

The rapid development of drugs against emerging and re-emerging viruses is required to prevent future pandemics. However, inhibitors usually take a long time to optimize. Here, to improve the optimization step, we used two heptad repeats (HR) in the spike protein (S protein) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a model and established a screening system for peptide-based inhibitors containing an α-helix region (SPICA). SPICA can be used to identify critical amino acid regions and evaluate the inhibitory effects of peptides as decoys. We further employed an artificial intelligence structure-prediction system (AlphaFold2) for the rapid analysis of structure–activity relationships. Here, we identified that critical amino acid regions, DVDLGD (amino acids 1163–1168 in the S protein), IQKEIDRLNE (1179–1188), and NLNESLIDL (1192–1200), played a pivotal role in SARS-CoV-2 fusion. Peptides containing these critical amino acid regions efficiently blocked viral replication. We also demonstrated that AlphaFold2 could successfully predict structures similar to the reported crystal and cryo-electron microscopy structures of the post-fusion form of the SARS-CoV-2 S protein. Notably, the predicted structures of the HR1 region and the peptide-based fusion inhibitors corresponded well with the antiviral effects of each fusion inhibitor. Thus, the combination of SPICA and AlphaFold2 is a powerful tool to design viral fusion inhibitors using only the amino-acid sequence of the fusion protein.

Graphical abstract: Helix-based screening with structure prediction using artificial intelligence has potential for the rapid development of peptide inhibitors targeting class I viral fusion

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Article information

Article type
Paper
Submitted
04 Sep 2023
Accepted
04 Nov 2023
First published
07 Nov 2023
This article is Open Access
Creative Commons BY-NC license

RSC Chem. Biol., 2024,5, 131-140

Helix-based screening with structure prediction using artificial intelligence has potential for the rapid development of peptide inhibitors targeting class I viral fusion

S. Suzuki, M. Kuroda, K. Aoki, K. Kawaji, Y. Hiramatsu, M. Sasano, A. Nishiyama, K. Murayama, E. N. Kodama, S. Oishi and H. Hayashi, RSC Chem. Biol., 2024, 5, 131 DOI: 10.1039/D3CB00166K

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