tetano
Editor, Senior Moderator
Protein Sci
. 2026 Feb;35(2):e70489.
doi: 10.1002/pro.70489.
Optimized ACE2-Fc fusion proteins with picomolar neutralization activity against highly evolved SARS-CoV-2 variants
Ferran Abancó[SUP] 1 2 [/SUP], Ferran Tarrés-Freixas[SUP] 1 2 3 4 [/SUP], Rosalba Lepore[SUP] 5 [/SUP], Elisa Molina-Molina[SUP] 1 [/SUP], Eloi Franco[SUP] 1 [/SUP], Rytis Boreika[SUP] 1 [/SUP], Edwards Pradenas[SUP] 1 [/SUP], Dàlia Raïch-Regué[SUP] 1 [/SUP], Itziar Erkizia[SUP] 1 [/SUP], Bonaventura Clotet[SUP] 1 6 [/SUP], Alfonso Valencia[SUP] 5 [/SUP], Júlia Vergara-Alert[SUP] 3 4 [/SUP], Joaquim Segalés[SUP] 3 7 [/SUP], Jorge Carrillo[SUP] 1 6 [/SUP], Nuria Izquierdo-Useros[SUP] 1 6 [/SUP], Julià Blanco[SUP] 1 2 6 8 [/SUP], Benjamin Trinité[SUP] 1 [/SUP]
Affiliations
The rapid evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has compromised the efficacy of many authorized monoclonal antibody products. This highlights the need for alternative strategies, especially for vulnerable populations such as immunocompromised individuals. Here, we optimized angiotensin-converting enzyme 2 (ACE2)-Fc fusion proteins by combining three engineering steps: in silico mutagenesis of the S protein binding interface to increase affinity, insertion of a flexible linker to improve protein stability and S protein accessibility, and generation of a tetrameric molecule to maximize avidity. Neutralizing activity was tested against a large panel of pre-Omicron and Omicron pseudoviruses and authentic viruses, including JN.1 and KP.2 variants. Optimized ACE2-Fc molecules demonstrated potent neutralizing activity, in the picomolar range, against all SARS-CoV-2 variants. Our molecules displayed similar potency but better resilience when compared to the monoclonal antibody Sipavibart. These findings support ACE2-Fc proteins as robust candidates for next-generation interventions against infection by an evolving SARS-CoV-2.
Keywords: ACE2; COVID‐19; Fc fusion protein; S protein; SARS‐CoV‐2; coronavirus; evolution; in silico mutagenesis; neutralizing activity.
. 2026 Feb;35(2):e70489.
doi: 10.1002/pro.70489.
Optimized ACE2-Fc fusion proteins with picomolar neutralization activity against highly evolved SARS-CoV-2 variants
Ferran Abancó[SUP] 1 2 [/SUP], Ferran Tarrés-Freixas[SUP] 1 2 3 4 [/SUP], Rosalba Lepore[SUP] 5 [/SUP], Elisa Molina-Molina[SUP] 1 [/SUP], Eloi Franco[SUP] 1 [/SUP], Rytis Boreika[SUP] 1 [/SUP], Edwards Pradenas[SUP] 1 [/SUP], Dàlia Raïch-Regué[SUP] 1 [/SUP], Itziar Erkizia[SUP] 1 [/SUP], Bonaventura Clotet[SUP] 1 6 [/SUP], Alfonso Valencia[SUP] 5 [/SUP], Júlia Vergara-Alert[SUP] 3 4 [/SUP], Joaquim Segalés[SUP] 3 7 [/SUP], Jorge Carrillo[SUP] 1 6 [/SUP], Nuria Izquierdo-Useros[SUP] 1 6 [/SUP], Julià Blanco[SUP] 1 2 6 8 [/SUP], Benjamin Trinité[SUP] 1 [/SUP]
Affiliations
- PMID: 41603290
- DOI: 10.1002/pro.70489
The rapid evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has compromised the efficacy of many authorized monoclonal antibody products. This highlights the need for alternative strategies, especially for vulnerable populations such as immunocompromised individuals. Here, we optimized angiotensin-converting enzyme 2 (ACE2)-Fc fusion proteins by combining three engineering steps: in silico mutagenesis of the S protein binding interface to increase affinity, insertion of a flexible linker to improve protein stability and S protein accessibility, and generation of a tetrameric molecule to maximize avidity. Neutralizing activity was tested against a large panel of pre-Omicron and Omicron pseudoviruses and authentic viruses, including JN.1 and KP.2 variants. Optimized ACE2-Fc molecules demonstrated potent neutralizing activity, in the picomolar range, against all SARS-CoV-2 variants. Our molecules displayed similar potency but better resilience when compared to the monoclonal antibody Sipavibart. These findings support ACE2-Fc proteins as robust candidates for next-generation interventions against infection by an evolving SARS-CoV-2.
Keywords: ACE2; COVID‐19; Fc fusion protein; S protein; SARS‐CoV‐2; coronavirus; evolution; in silico mutagenesis; neutralizing activity.