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