Abstract
The ongoing COVID-19 pandemic has had great societal and health consequences. Despite the availability of vaccines, infection rates remain high due to immune evasive Omicron sublineages. Broad-spectrum antivirals are needed to safeguard against emerging variants and future pandemics. We used mRNA display under a reprogrammed genetic code to find a spike-targeting macrocyclic peptide that inhibits SARS-CoV-2 Wuhan strain infection and also pseudoviruses containing spike proteins of SARS-CoV-2 variants or related sarbecoviruses. Structural and bioinformatic analyses reveal a conserved binding pocket between the receptor binding domain and other domains, distal to the ACE2 receptor-interaction site. Collectively, our data reveal a hitherto unexplored site of vulnerability in sarbecoviruses that can be targeted by peptides and potentially other drug-like molecules.
One-Sentence Summary We identify a conserved site on the SARS-CoV-2 spike that can be targeted by a broadly neutralizing macrocyclic peptide.
Competing Interest Statement
VT, DLH, FJMK and SAKJ are named inventors on a patent application that has been filed on 15 July 2022 entitled: Antiviral cyclic compounds (EP22185235; patent applicants: Universiteit Utrecht Holdings B.V. on behalf of Utrecht University). ID is an employee of Thermo Fisher Scientific. The remaining authors declare that they have no competing interests.
Footnotes
Minor corrections to errors in figures and text, addition of accession numbers for structures and sequencing data
