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Engineered dityrosine-bonding of the RSV prefusion F protein imparts stability and potency advantages

Author

Listed:
  • Sonal V. Gidwani

    (Calder Biosciences Inc., Brooklyn Army Terminal)

  • Devarshi Brahmbhatt

    (Calder Biosciences Inc., Brooklyn Army Terminal)

  • Aaron Zomback

    (Calder Biosciences Inc., Brooklyn Army Terminal)

  • Mamie Bassie

    (Calder Biosciences Inc., Brooklyn Army Terminal)

  • Jennifer Martinez

    (Calder Biosciences Inc., Brooklyn Army Terminal)

  • Jian Zhuang

    (Calder Biosciences Inc., Brooklyn Army Terminal
    Donald and Barbara Zucker School of Medicine at Hofstra/Northwell)

  • John Schulze

    (University of California, Davis)

  • Jason S. McLellan

    (University of Texas at Austin, College of Natural Sciences)

  • Roberto Mariani

    (Calder Biosciences Inc., Brooklyn Army Terminal
    CUNY Kingsborough Community College)

  • Peter Alff

    (Calder Biosciences Inc., Brooklyn Army Terminal)

  • Daniela Frasca

    (University of Miami)

  • Bonnie B. Blomberg

    (University of Miami)

  • Christopher P. Marshall

    (Calder Biosciences Inc., Brooklyn Army Terminal)

  • Mark A. Yondola

    (Calder Biosciences Inc., Brooklyn Army Terminal)

Abstract

Viral fusion proteins facilitate cellular infection by fusing viral and cellular membranes, which involves dramatic transitions from their pre- to postfusion conformations. These proteins are among the most protective viral immunogens, but they are metastable which often makes them intractable as subunit vaccine targets. Adapting a natural enzymatic reaction, we harness the structural rigidity that targeted dityrosine crosslinks impart to covalently stabilize fusion proteins in their native conformations. We show that the prefusion conformation of respiratory syncytial virus fusion protein can be stabilized with two engineered dityrosine crosslinks (DT-preF), markedly improving its stability and shelf-life. Furthermore, it has 11X greater potency as compared with the DS-Cav1 stabilized prefusion F protein in immunogenicity studies and overcomes immunosenescence in mice with simply a high-dose formulation on alum.

Suggested Citation

  • Sonal V. Gidwani & Devarshi Brahmbhatt & Aaron Zomback & Mamie Bassie & Jennifer Martinez & Jian Zhuang & John Schulze & Jason S. McLellan & Roberto Mariani & Peter Alff & Daniela Frasca & Bonnie B. B, 2024. "Engineered dityrosine-bonding of the RSV prefusion F protein imparts stability and potency advantages," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46295-8
    DOI: 10.1038/s41467-024-46295-8
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    References listed on IDEAS

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    1. Christopher C. Stobart & Christina A. Rostad & Zunlong Ke & Rebecca S. Dillard & Cheri M. Hampton & Joshua D. Strauss & Hong Yi & Anne L. Hotard & Jia Meng & Raymond J. Pickles & Kaori Sakamoto & Suji, 2016. "A live RSV vaccine with engineered thermostability is immunogenic in cotton rats despite high attenuation," Nature Communications, Nature, vol. 7(1), pages 1-12, December.
    2. Anders Krarup & Daphné Truan & Polina Furmanova-Hollenstein & Lies Bogaert & Pascale Bouchier & Ilona J. M. Bisschop & Myra N. Widjojoatmodjo & Roland Zahn & Hanneke Schuitemaker & Jason S. McLellan &, 2015. "A highly stable prefusion RSV F vaccine derived from structural analysis of the fusion mechanism," Nature Communications, Nature, vol. 6(1), pages 1-12, November.
    3. Christopher M. Elvin & Andrew G. Carr & Mickey G. Huson & Jane M. Maxwell & Roger D. Pearson & Tony Vuocolo & Nancy E. Liyou & Darren C. C. Wong & David J. Merritt & Nicholas E. Dixon, 2005. "Synthesis and properties of crosslinked recombinant pro-resilin," Nature, Nature, vol. 437(7061), pages 999-1002, October.
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