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Structure-based design of prefusion-stabilized human metapneumovirus fusion proteins

Author

Listed:
  • Ching-Lin Hsieh

    (The University of Texas at Austin)

  • Scott A. Rush

    (The University of Texas at Austin)

  • Concepcion Palomo

    (Centro Nacional de Microbiología, Instituto de Salud Carlos III)

  • Chia-Wei Chou

    (The University of Texas at Austin)

  • Whitney Pickens

    (The University of Texas at Austin)

  • Vicente Más

    (Centro Nacional de Microbiología, Instituto de Salud Carlos III)

  • Jason S. McLellan

    (The University of Texas at Austin)

Abstract

The human metapneumovirus (hMPV) fusion (F) protein is essential for viral entry and is a key target of neutralizing antibodies and vaccine development. The prefusion conformation is thought to be the optimal vaccine antigen, but previously described prefusion F proteins expressed poorly and were not well stabilized. Here, we use structures of hMPV F to guide the design of 42 variants containing stabilizing substitutions. Through combinatorial addition of disulfide bonds, cavity-filling substitutions, and improved electrostatic interactions, we describe a prefusion-stabilized F protein (DS-CavEs2) that expresses at 15 mg/L and has a melting temperature of 71.9 °C. Crystal structures of two prefusion-stabilized hMPV F variants reveal that antigenic surfaces are largely unperturbed. Importantly, immunization of mice with DS-CavEs2 elicits significantly higher neutralizing antibody titers against hMPV A1 and B1 viruses than postfusion F. The improved properties of DS-CavEs2 will advance the development of hMPV vaccines and the isolation of therapeutic antibodies.

Suggested Citation

  • Ching-Lin Hsieh & Scott A. Rush & Concepcion Palomo & Chia-Wei Chou & Whitney Pickens & Vicente Más & Jason S. McLellan, 2022. "Structure-based design of prefusion-stabilized human metapneumovirus fusion proteins," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28931-3
    DOI: 10.1038/s41467-022-28931-3
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    References listed on IDEAS

    as
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    3. Michael B. Battles & Vicente Más & Eduardo Olmedillas & Olga Cano & Mónica Vázquez & Laura Rodríguez & José A. Melero & Jason S. McLellan, 2017. "Structure and immunogenicity of pre-fusion-stabilized human metapneumovirus F glycoprotein," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    4. 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.
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    Cited by:

    1. Karen J. Gonzalez & Jiachen Huang & Miria F. Criado & Avik Banerjee & Stephen M. Tompkins & Jarrod J. Mousa & Eva-Maria Strauch, 2024. "A general computational design strategy for stabilizing viral class I fusion proteins," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Mark J. G. Bakkers & Tina Ritschel & Machteld Tiemessen & Jacobus Dijkman & Angelo A. Zuffianò & Xiaodi Yu & Daan Overveld & Lam Le & Richard Voorzaat & Marlies M. Haaren & Martijn Man & Sem Tamara & , 2024. "Efficacious human metapneumovirus vaccine based on AI-guided engineering of a closed prefusion trimer," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Ching-Lin Hsieh & Sarah R. Leist & Emily Happy Miller & Ling Zhou & John M. Powers & Alexandra L. Tse & Albert Wang & Ande West & Mark R. Zweigart & Jonathan C. Schisler & Rohit K. Jangra & Kartik Cha, 2024. "Prefusion-stabilized SARS-CoV-2 S2-only antigen provides protection against SARS-CoV-2 challenge," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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