tetano
Editor, Senior Moderator
Commun Biol
. 2025 Oct 6;8(1):1428.
doi: 10.1038/s42003-025-08819-w. Development of an ultrahigh affinity, trimeric ACE2 biologic as a universal SARS-CoV-2 antagonist
Juliet Gonzales[SUP] #[/SUP][SUP] 1 2 [/SUP], Tynan Young[SUP] #[/SUP][SUP] 2 [/SUP], Hyeran Choi[SUP] 2 [/SUP], Miso Park[SUP] 2 [/SUP], Yead Jewel[SUP] 2 [/SUP], Chengcheng Fan[SUP] 3 [/SUP], Rahul Purohit[SUP] 2 [/SUP], Pamela J Bjorkman[SUP] 3 [/SUP], John C Williams[SUP] 4 5 [/SUP]
Affiliations
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the COVID-19 pandemic, utilizes membrane-bound, angiotensin-converting enzyme II (ACE2) for internalization and infection. We describe the development of a biologic that takes advantage of the proximity of the N-terminus of bound ACE2 to the three-fold symmetry axis of the spike protein to create an ultrapotent, trivalent ACE2 entry antagonist. Distinct disulfide bonds were added to enhance serum stability and a single point mutation was introduced to eliminate enzymatic activity. Through surface plasmon resonance, pseudovirus neutralization assays, and single-particle cryo-electron microscopy, we show this antagonist binds to and inhibits SARS-CoV-2 variants. We further show the antagonist binds to and inhibits a 2003 SARS-CoV-1 strain. Collectively, structural insight has allowed us to design a universal trivalent antagonist against all variants of SARS-CoV-2 tested, suggesting it will be active against the emergence of future mutants.
. 2025 Oct 6;8(1):1428.
doi: 10.1038/s42003-025-08819-w. Development of an ultrahigh affinity, trimeric ACE2 biologic as a universal SARS-CoV-2 antagonist
Juliet Gonzales[SUP] #[/SUP][SUP] 1 2 [/SUP], Tynan Young[SUP] #[/SUP][SUP] 2 [/SUP], Hyeran Choi[SUP] 2 [/SUP], Miso Park[SUP] 2 [/SUP], Yead Jewel[SUP] 2 [/SUP], Chengcheng Fan[SUP] 3 [/SUP], Rahul Purohit[SUP] 2 [/SUP], Pamela J Bjorkman[SUP] 3 [/SUP], John C Williams[SUP] 4 5 [/SUP]
Affiliations
- PMID: 41053501
- DOI: 10.1038/s42003-025-08819-w
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the COVID-19 pandemic, utilizes membrane-bound, angiotensin-converting enzyme II (ACE2) for internalization and infection. We describe the development of a biologic that takes advantage of the proximity of the N-terminus of bound ACE2 to the three-fold symmetry axis of the spike protein to create an ultrapotent, trivalent ACE2 entry antagonist. Distinct disulfide bonds were added to enhance serum stability and a single point mutation was introduced to eliminate enzymatic activity. Through surface plasmon resonance, pseudovirus neutralization assays, and single-particle cryo-electron microscopy, we show this antagonist binds to and inhibits SARS-CoV-2 variants. We further show the antagonist binds to and inhibits a 2003 SARS-CoV-1 strain. Collectively, structural insight has allowed us to design a universal trivalent antagonist against all variants of SARS-CoV-2 tested, suggesting it will be active against the emergence of future mutants.