Potency of Fusion-Inhibitory Lipopeptides against SARS-CoV-2 Variants of Concern

Katharina S. Schmitz, Daryl Geers, Rory D. de Vries, T. Francesca Bovier, Anna Z. Mykytyn, Corine H. Geurts van Kessel, Bart L. Haagmans, Matteo Porotto, Rik L. de Swart, Anne Moscona*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

The ability of SARS-CoV-2 to evolve in response to selective pressures poses a challenge to vaccine and antiviral efficacy. The S1 subunit of the spike (S) protein contains the receptor-binding domain and is therefore under selective pressure to evade neutralizing antibodies elicited by vaccination or infection. In contrast, the S2 subunit of S is only transiently exposed after receptor binding, which makes it a less efficient target for antibodies. As a result, S2 has a lower mutational frequency than S1. We recently described monomeric and dimeric SARS-CoV-2 fusion-inhibitory lipopeptides that block viral infection by interfering with S2 conformational rearrangements during viral entry. Importantly, a dimeric lipopeptide was shown to block SARS-CoV-2 transmission between ferrets in vivo. Because the S2 subunit is relatively conserved in newly emerging SARS-CoV-2 variants of concern (VOCs), we hypothesize that fusion-inhibitory lipopeptides are cross-protective against infection with VOCs. Here, we directly compared the in vitro efficacies of two fusion-inhibitory lipopeptides against VOC, in comparison with a set of seven postvaccination sera (two doses) and a commercial monoclonal antibody preparation. For the beta, delta, and omicron VOCs, it has been reported that convalescent and postvaccination sera are less potent in virus neutralization assays. Both fusion-inhibitory lipopeptides were equally effective against all five VOCs compared to ancestral virus, whereas postvaccination sera and therapeutic monoclonal antibody lost potency to newer VOCs, in particular to omicron BA.1 and BA.2. The neutralizing activity of the lipopeptides is consistent, and they can be expected to neutralize future VOCs based on their mechanism of action.

Original languageEnglish
JournalmBio
Volume13
Issue number3
DOIs
Publication statusPublished - Jun 2022

Bibliographical note

Funding Information:
This work was supported by funding from the National Institutes of Health (RO1 AI160961 to A.M. and RO1 AI160953 to M.P.) and the Sharon Golub Fund at Columbia University Medical Center.

Publisher Copyright:
© 2022 Schmitz et al.

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