tetano
Editor, Senior Moderator
Cell Rep
. 2025 May 30;44(6):115760.
doi: 10.1016/j.celrep.2025.115760. Online ahead of print. Designed miniproteins potently inhibit and protect against MERS-CoV
Robert J Ragotte[SUP] 1 [/SUP], M Alejandra Tortorici[SUP] 2 [/SUP], Nicholas J Catanzaro[SUP] 3 [/SUP], Amin Addetia[SUP] 2 [/SUP], Brian Coventry[SUP] 1 [/SUP], Heather M Froggatt[SUP] 3 [/SUP], Jimin Lee[SUP] 2 [/SUP], Cameron Stewart[SUP] 2 [/SUP], Jack T Brown[SUP] 2 [/SUP], Inna Goreshnik[SUP] 1 [/SUP], Jeremiah N Sims[SUP] 1 [/SUP], Lukas F Milles[SUP] 1 [/SUP], Basile I M Wicky[SUP] 1 [/SUP], Matthias Glögl[SUP] 1 [/SUP], Stacey Gerben[SUP] 1 [/SUP], Alex Kang[SUP] 1 [/SUP], Asim K Bera[SUP] 1 [/SUP], William Sharkey[SUP] 2 [/SUP], Alexandra Schäfer[SUP] 3 [/SUP], Jack R Harkema[SUP] 4 [/SUP], Ralph S Baric[SUP] 5 [/SUP], David Baker[SUP] 6 [/SUP], David Veesler[SUP] 7 [/SUP]
Affiliations
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.
Keywords: CP: Immunology; MERS-CoV; VSV-neutralization; X-ray crystallography; coronaviruses; cryo-EM; fusion assays; miniproteins; protein design; spike glycoprotein; therapeutics.
. 2025 May 30;44(6):115760.
doi: 10.1016/j.celrep.2025.115760. Online ahead of print. Designed miniproteins potently inhibit and protect against MERS-CoV
Robert J Ragotte[SUP] 1 [/SUP], M Alejandra Tortorici[SUP] 2 [/SUP], Nicholas J Catanzaro[SUP] 3 [/SUP], Amin Addetia[SUP] 2 [/SUP], Brian Coventry[SUP] 1 [/SUP], Heather M Froggatt[SUP] 3 [/SUP], Jimin Lee[SUP] 2 [/SUP], Cameron Stewart[SUP] 2 [/SUP], Jack T Brown[SUP] 2 [/SUP], Inna Goreshnik[SUP] 1 [/SUP], Jeremiah N Sims[SUP] 1 [/SUP], Lukas F Milles[SUP] 1 [/SUP], Basile I M Wicky[SUP] 1 [/SUP], Matthias Glögl[SUP] 1 [/SUP], Stacey Gerben[SUP] 1 [/SUP], Alex Kang[SUP] 1 [/SUP], Asim K Bera[SUP] 1 [/SUP], William Sharkey[SUP] 2 [/SUP], Alexandra Schäfer[SUP] 3 [/SUP], Jack R Harkema[SUP] 4 [/SUP], Ralph S Baric[SUP] 5 [/SUP], David Baker[SUP] 6 [/SUP], David Veesler[SUP] 7 [/SUP]
Affiliations
- PMID: 40450691
- DOI: 10.1016/j.celrep.2025.115760
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.
Keywords: CP: Immunology; MERS-CoV; VSV-neutralization; X-ray crystallography; coronaviruses; cryo-EM; fusion assays; miniproteins; protein design; spike glycoprotein; therapeutics.