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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 1 2 , Ferran Tarrés-Freixas 1 2 3 4 , Rosalba Lepore 5 , Elisa Molina-Molina 1 , Eloi Franco 1 , Rytis Boreika 1 , Edwards Pradenas 1 , Dàlia Raïch-Regué 1 , Itziar Erkizia 1 , Bonaventura Clotet 1 6 , Alfonso Valencia 5 , Júlia Vergara-Alert 3 4 , Joaquim Segalés 3 7 , Jorge Carrillo 1 6 , Nuria Izquierdo-Useros 1 6 , Julià Blanco 1 2 6 8 , Benjamin Trinité 1
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 1 2 , Ferran Tarrés-Freixas 1 2 3 4 , Rosalba Lepore 5 , Elisa Molina-Molina 1 , Eloi Franco 1 , Rytis Boreika 1 , Edwards Pradenas 1 , Dàlia Raïch-Regué 1 , Itziar Erkizia 1 , Bonaventura Clotet 1 6 , Alfonso Valencia 5 , Júlia Vergara-Alert 3 4 , Joaquim Segalés 3 7 , Jorge Carrillo 1 6 , Nuria Izquierdo-Useros 1 6 , Julià Blanco 1 2 6 8 , Benjamin Trinité 1
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.