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| Title | Development of an ultrahigh affinity, trimeric ACE2 biologic as a universal SARS-CoV-2 antagonist. |
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| Journal, issue, pages | Commun Biol, Vol. 8, Issue 1, Page 1428, Year 2025 |
| Publish date | Oct 6, 2025 |
Authors | Juliet Gonzales / Tynan Young / Hyeran Choi / Miso Park / Yead Jewel / Chengcheng Fan / Rahul Purohit / Pamela J Bjorkman / John C Williams / ![]() |
| PubMed Abstract | 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. ...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. |
External links | Commun Biol / PubMed:41053501 / PubMed Central |
| Methods | EM (single particle) / X-ray diffraction |
| Resolution | 1.4 - 3.73 Å |
| Structure data | EMDB-44724, PDB-9bnd: EMDB-44725, PDB-9bne: EMDB-44726, PDB-9bnf: EMDB-44727, PDB-9bng: ![]() PDB-9bnb: ![]() PDB-9bnc: |
| Chemicals | ![]() ChemComp-HOH: ![]() ChemComp-SO4: ![]() ChemComp-PEG: ![]() ChemComp-NAG: |
| Source |
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Keywords | STRUCTURAL PROTEIN / Trimer / Disulfide / Biologic scaffold / VIRAL PROTEIN/ANTAGONIST / trimeric antagonist SARS-CoV-2 complex / PROTEIN BINDING / VIRAL PROTEIN-ANTAGONIST complex |
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homo sapiens (human)
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