Development of an ultrahigh affinity, trimeric ACE2 biologic as a universal SARS-CoV-2 antagonist

  • Commun Biol. 2025 Oct 6;8(1):1428. doi: 10.1038/s42003-025-08819-w.
Juliet Gonzales  #  1  2 ,  Tynan Young  #  2 ,  Hyeran Choi  2 ,  Miso Park  2 ,  Yead Jewel  2 ,  Chengcheng Fan  3 ,  Rahul Purohit  2 ,  Pamela J Bjorkman  3 ,  John C Williams  4  5
Affiliations
  • 1. Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, CA, USA.
  • 2. Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA, USA.
  • 3. Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
  • 4. Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, CA, USA. [email protected].
  • 5. Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA, USA. [email protected].
  • # Contributed equally.
PMID: 41053501 DOI: 10.1038/s42003-025-08819-w
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. 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.

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