Designed miniproteins potently inhibit and protect against MERS-CoV

Ragotte, R. J.; Tortorici, M. A.; Cantazaro, N. J.; Addetia, A.; Coventry, B.; Froggatt, H. M.; Lee, J.; Stewart, C.; Brown, J. T.; Goreshnik, I.; Sims, J. N.; Milles, L. F.; Wicky, B. I.; Gloegl, M.; Gerben, S.; Kang, A.; Bera, A. K.; Sharkey, W.; Schaefer, A.; Baric, R. S.; Baker, D.; Veesler, D.

doi:10.1101/2024.11.03.621760

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bioRxiv · 10.1101/2024.11.03.621760

Designed miniproteins potently inhibit and protect against MERS-CoV

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Abstract

Middle-East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic pathogen with 36% case-fatality rate in humans. No vaccines or specific therapeutics are currently approved to use in humans or the camel host reservoir. Here, we computationally designed monomeric and homo-oligomeric miniproteins binding 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 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 future clinical development as a next-generation countermeasure against this virus with pandemic potential.

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Ragotte, R. J., Tortorici, M. A., Cantazaro, N. J., Addetia, A., Coventry, B., Froggatt, H. M., Lee, J., Stewart, C., Brown, J. T., Goreshnik, I., Sims, J. N., Milles, L. F., Wicky, B. I., Gloegl, M., Gerben, S., Kang, A., Bera, A. K., Sharkey, W., Schaefer, A., Baric, R. S., Baker, D., Veesler, D.. 2024-11-04. Designed miniproteins potently inhibit and protect against MERS-CoV. https://doi.org/10.1101/2024.11.03.621760

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