A computationally designed ACE2 decoy has broad efficacy against SARS-CoV-2 omicron variants and related viruses in vitro and in vivo

• Published in: Communications Biology Vol. 6; no. 1; pp. 513 - 16
• Main Authors: Havranek, Brandon, Lindsey, Graeme Walker, Higuchi, Yusuke, Itoh, Yumi, Suzuki, Tatsuya, Okamoto, Toru, Hoshino, Atsushi, Procko, Erik, Islam, Shahidul M.
• Format: Journal Article
• Language: English
• Published: London Springer Science and Business Media LLC 12.05.2023; Nature Publishing Group UK; Nature Publishing Group; Nature Portfolio
• Subjects: 631/114/469; 631/154/51/2314; 631/57/2266; 82; 82/80; 82/81; 82/83; 96; 96/31; ACE2; Affinity; Angiotensin-converting enzyme 2; Angiotensin-Converting Enzyme 2 - genetics; Angiotensin-Converting Enzyme 2 - therapeutic use; antibodies; Antibodies, Monoclonal; Biology; Biology (General); Biomedical and Life Sciences; Computer applications; COVID-19; Design; Humans; Life Sciences; Medical Biochemistry; Medical Sciences; Medicine and Health Sciences; monoclonal; Monoclonal antibodies; Protein Engineering; QH301-705.5; SARS-CoV-2; SARS-CoV-2 - genetics; Severe acute respiratory syndrome coronavirus 2; Vaccination
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-023-04860-9

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. A computational design strategy is used to develop an affinity-enhanced ACE2 decoy, which is shown to be effective at neutralizing omicron subvariants in vitro and in vivo.