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

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. Blomberg, Christopher P. Marshall and Mark A. Yondola ()
Additional contact information
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
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
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

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46295-8

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