Designed miniproteins potently inhibit and protect against MERS-CoV
Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic pathogen with a 36% case-fatality rate in humans. No vaccines or specific therapeutics are currently approved for use in humans or the camel host reservoir. Here, we computationally designed monomeric and homo-oligomeric miniproteins that bind with high affinity to the MERS-CoV spike (S) glycoprotein, the main target of neutralizing antibodies and vaccine development. We show that these miniproteins broadly neutralize a panel of MERS-CoV S variants, spanning the known antigenic diversity of this pathogen, by targeting a conserved site in the receptor-binding domain (RBD). The miniproteins directly compete with binding of the dipeptidylpeptidase 4 (DPP4) receptor to MERS-CoV S, thereby blocking viral attachment to the host entry receptor and subsequent membrane fusion. Intranasal administration of a lead miniprotein provides prophylactic protection against stringent MERS-CoV challenge in mice, motivating its future clinical development as a next-generation countermeasure against this virus with pandemic potential.
Authors
- Robert J. Ragotte (ORCID: https://orcid.org/0000-0002-6463-1595)
- Brian Coventry (ORCID: https://orcid.org/0000-0002-6910-6255)
- M. Alejandra Tortorici (ORCID: https://orcid.org/0000-0002-2260-2577)
- Jack T Brown (ORCID: https://orcid.org/0000-0002-6159-2148)
- Jack R. Harkema (ORCID: https://orcid.org/0000-0003-4682-0824)
- Asim K. Bera (ORCID: https://orcid.org/0000-0001-9473-2912)
- Nicholas J. Catanzaro
- William W. Sharkey
- Amin Addetia (ORCID: https://orcid.org/0000-0001-6703-3841)
- Basile I. M. Wicky (ORCID: https://orcid.org/0000-0002-2501-7875)
- Cameron Stewart (ORCID: https://orcid.org/0000-0002-2786-6256)
- Lukas F. Milles (ORCID: https://orcid.org/0000-0001-8417-3205)
- Jeremiah N Sims
- Alex Kang (ORCID: https://orcid.org/0000-0001-5487-0499)
- Jimin Lee (ORCID: https://orcid.org/0000-0001-5849-7732)
- Inna Goreshnik (ORCID: https://orcid.org/0000-0002-9254-9249)
- Matthias Glögl (ORCID: https://orcid.org/0000-0001-7011-8184)
- David Veesler (ORCID: https://orcid.org/0000-0002-6019-8675)
- Heather M. Froggatt (ORCID: https://orcid.org/0000-0001-7785-0976)
- David Baker (ORCID: https://orcid.org/0000-0002-6811-8238)
- Stacey Gerben
- Ralph S. Baric
- Alexandra Schäfer
Institutions
- University of North Carolina at Chapel Hill (US)
- University of North Carolina Health Care (US)
- Howard Hughes Medical Institute (US)
- University of Washington (US)
- University of Washington Medical Center (US)
- Michigan State University (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-05-30
- DOI
- https://doi.org/10.1016/j.celrep.2025.115760
- Citations
- 7
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 8.38
Funders
- Howard Hughes Medical Institute
- U.S. Department of Energy
- Washington Research Foundation
- Michigan State University
- University of Washington
- Office of Science
- College of Engineering, Michigan State University
- National Institute of Allergy and Infectious Diseases
- Argonne National Laboratory