A Computationally Designed ACE2 Decoy Has Broad Efficacy Against SARS-CoV-2 Omicron Variants and Related Viruses in Vitro and in Vivo

Authors

Brandon Havranek, Thomas Jefferson UniversityFollow
Graeme Walker Lindsey
Yusuke Higuchi
Yumi Itoh
Tatsuya Suzuki
Toru Okamoto
Atsushi Hoshino
Erik Procko
Shahidul M. Islam

Document Type

Article

Publication Date

5-12-2023

Comments

This article is the author's final published version in Communications Biology, Volume 6, 2023, Article number 513.

The published version is available at https://doi.org/10.1038/s42003-023-04860-9. Copyright © The Author(s) 2023.

Abstract

SARS-CoV-2, especially B.1.1.529/omicron and its sublineages, continues to mutate to evade monoclonal antibodies and antibodies elicited by vaccination. Affinity-enhanced soluble ACE2 (sACE2) is an alternative strategy that works by binding the SARS-CoV-2 S protein, acting as a 'decoy' to block the interaction between the S and human ACE2. Using a computational design strategy, we designed an affinity-enhanced ACE2 decoy, FLIF, that exhibited tight binding to SARS-CoV-2 delta and omicron variants. Our computationally calculated absolute binding free energies (ABFE) between sACE2:SARS-CoV-2 S proteins and their variants showed excellent agreement to binding experiments. FLIF displayed robust therapeutic utility against a broad range of SARS-CoV-2 variants and sarbecoviruses, and neutralized omicron BA.5 in vitro and in vivo. Furthermore, we directly compared the in vivo therapeutic efficacy of wild-type ACE2 (non-affinity enhanced ACE2) against FLIF. A few wild-type sACE2 decoys have shown to be effective against early circulating variants such as Wuhan in vivo. Our data suggest that moving forward, affinity-enhanced ACE2 decoys like FLIF may be required to combat evolving SARS-CoV-2 variants. The approach described herein emphasizes how computational methods have become sufficiently accurate for the design of therapeutics against viral protein targets. Affinity-enhanced ACE2 decoys remain highly effective at neutralizing omicron subvariants.

Recommended Citation

Havranek, Brandon; Lindsey, Graeme Walker; Higuchi, Yusuke; Itoh, Yumi; Suzuki, Tatsuya; Okamoto, Toru; Hoshino, Atsushi; Procko, Erik; and Islam, Shahidul M., "A Computationally Designed ACE2 Decoy Has Broad Efficacy Against SARS-CoV-2 Omicron Variants and Related Viruses in Vitro and in Vivo" (2023). SKMC Student Presentations and Publications. Paper 2.
https://jdc.jefferson.edu/skmcstudentworks/2

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

Language

English