Identification of motif-based interactions between SARS-CoV-2 protein domains and human peptide ligands pinpoint antiviral targets

Filip Mihalič, Caroline Benz, Eszter Kassa, Richard Lindqvist, Leandro Simonetti, Raviteja Inturi, Hanna Aronsson, Eva Andersson, Celestine N. Chi, Norman E. Davey, Anna K. Överby, Per Jemth () and Ylva Ivarsson ()
Additional contact information
Filip Mihalič: Uppsala University
Caroline Benz: Uppsala University
Eszter Kassa: Uppsala University
Richard Lindqvist: Umeå University
Leandro Simonetti: Uppsala University
Raviteja Inturi: Uppsala University
Hanna Aronsson: Uppsala University
Eva Andersson: Uppsala University
Celestine N. Chi: Uppsala University
Norman E. Davey: The Institute of Cancer Research
Anna K. Överby: Umeå University
Per Jemth: Uppsala University
Ylva Ivarsson: Uppsala University

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract The virus life cycle depends on host-virus protein-protein interactions, which often involve a disordered protein region binding to a folded protein domain. Here, we used proteomic peptide phage display (ProP-PD) to identify peptides from the intrinsically disordered regions of the human proteome that bind to folded protein domains encoded by the SARS-CoV-2 genome. Eleven folded domains of SARS-CoV-2 proteins were found to bind 281 peptides from human proteins, and affinities of 31 interactions involving eight SARS-CoV-2 protein domains were determined (KD ∼ 7-300 μM). Key specificity residues of the peptides were established for six of the interactions. Two of the peptides, binding Nsp9 and Nsp16, respectively, inhibited viral replication. Our findings demonstrate how high-throughput peptide binding screens simultaneously identify potential host-virus interactions and peptides with antiviral properties. Furthermore, the high number of low-affinity interactions suggest that overexpression of viral proteins during infection may perturb multiple cellular pathways.

Date: 2023
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DOI: 10.1038/s41467-023-41312-8

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