Issue 46, 2024

Cyclic peptides targeting the SARS-CoV-2 programmed ribosomal frameshifting RNA from a multiplexed phage display library

Abstract

RNA provides the genetic blueprint for many pathogenic viruses, including SARS-CoV-2. The propensity of RNA to fold into specific tertiary structures enables the biomolecular recognition of cavities and crevices suited for the binding of drug-like molecules. Despite increasing interest in RNA as a target for chemical biology and therapeutic applications, the development of molecules that recognize RNA with high affinity and specificity represents a significant challenge. Here, we report a strategy for the discovery and selection of RNA-targeted macrocyclic peptides derived from combinatorial libraries of peptide macrocycles displayed by bacteriophages. Specifically, a platform for phage display of macrocyclic organo-peptide hybrids (MOrPH-PhD) was combined with a diverse set of non-canonical amino acid-based cyclization modules to produce large libraries of 107 structurally diverse, genetically encoded peptide macrocycles. These libraries were panned against the −1 programmed ribosomal frameshifting stimulatory sequence (FSS) RNA pseudoknot of SARS-CoV-2, which revealed specific macrocyclic peptide sequences that bind this essential motif with high affinity and selectivity. Peptide binding localizes to the FSS dimerization loop based on chemical modification analysis and binding assays and the cyclic peptides show specificity toward the target RNA over unrelated RNA pseudoknots. This work introduces a novel system for the generation and high-throughput screening of topologically diverse cyclopeptide scaffolds (multiplexed MOrPH-PhD), and it provides a blueprint for the exploration and evolution of genetically encoded macrocyclic peptides that target specific RNAs.

Graphical abstract: Cyclic peptides targeting the SARS-CoV-2 programmed ribosomal frameshifting RNA from a multiplexed phage display library

Supplementary files

Article information

Article type
Edge Article
Submitted
19 Jun 2024
Accepted
03 Oct 2024
First published
17 Oct 2024
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2024,15, 19520-19533

Cyclic peptides targeting the SARS-CoV-2 programmed ribosomal frameshifting RNA from a multiplexed phage display library

J. A. Iannuzzelli, R. Bonn, A. S. Hong, A. S. Anitha, J. L. Jenkins, J. E. Wedekind and R. Fasan, Chem. Sci., 2024, 15, 19520 DOI: 10.1039/D4SC04026K

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