Toward Fusion-Inhibitory Peptides that Block SARS-CoV-2 Infection
Samuel Gellman
Professor of Chemistry, University of Wisconsin-Madison
SARS-CoV-2 infection requires fusion of the viral envelope with a host cell membrane. The viral spike protein (S) orchestrates fusion via a class I mechanism. Fusion of the lipid bilayers is driven by dramatic rearrangements of the S trimer, which lead to formation of a highly stable “six-helix bundle” (6HB) post-fusion assembly. In general, 6HB assemblies contain a core trimer of α-helices formed by N-terminal heptad repeat (HRN) segments. This core is surrounded by three HRC segments that are entirely or partially helical, depending on the virus. As is often true for class I viral fusion proteins, long peptides derived from the HRC domain of the native fusion protein can inhibit SARS-CoV-2 entry. Our laboratory is part of a collaborative team that is developing backbone-modified fusion inhibitors intended to block SARS-CoV-2 infection and resist proteolytic degradation. This effort builds upon our experience with inhibitors of other enveloped viruses, including HIV and HPIV3.
Sam Gellman is the Ralph F. Hirschmann Professor of Chemistry and a Vilas Research Professor at the University of Wisconsin - Madison. Major interests in his research program focus on polypeptides in diverse forms and settings. Specific topics include elucidation of the origins of peptide and protein folding preferences, development of unnatural peptidic oligomers that display protein-like conformational behavior ("foldamers"), and the engineering of foldamers that can inhibit deleterious protein-protein interactions or mimic the receptor-activation behavior of peptide hormones.