Cell reports · 2025
Designed miniproteins potently inhibit and protect against MERS-CoV.
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Ragotte Robert J, Tortorici M Alejandra, Catanzaro Nicholas J, Addetia Amin, Coventry Brian, Froggatt Heather M, Lee Jimin, Stewart Cameron, Brown Jack T, Goreshnik Inna, Sims Jeremiah N, Milles Lukas F, Wicky Basile I M, Glögl Matthias, Gerben Stacey, Kang Alex, Bera Asim K, Sharkey William, Schäfer Alexandra, Harkema Jack R, Baric Ralph S, Baker David, Veesler David
Аннотация
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.