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, Baric Ralph S, Baker David, Veesler David
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
bioRxiv. 2024 Nov 4:2024.11.03.621760. doi: 10.1101/2024.11.03.621760.
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.
中东呼吸综合征冠状病毒（MERS-CoV）是一种人畜共患病原体，在人类中的病死率为36%。目前尚无获批用于人类或骆驼宿主的疫苗或特异性治疗方法。在此，我们通过计算机设计了与中东呼吸综合征冠状病毒刺突（S）糖蛋白具有高亲和力结合的单体和同聚体微型蛋白，该糖蛋白是中和抗体和疫苗开发的主要靶点。我们表明，这些微型蛋白通过靶向受体结合域（RBD）中的保守位点，广泛中和一组中东呼吸综合征冠状病毒S变体，涵盖了该病原体已知的抗原多样性。这些微型蛋白直接竞争二肽基肽酶4（DPP4）受体与中东呼吸综合征冠状病毒S的结合，从而阻断病毒与宿主进入受体的附着以及随后的膜融合。鼻内给予一种先导微型蛋白可对小鼠面临的严峻中东呼吸综合征冠状病毒攻击提供预防性保护，这激发了其作为针对这种具有大流行潜力病毒的下一代对策进行未来临床开发的可能性。
