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

Ching-Lin Hsieh, Scott A. Rush, Concepcion Palomo, Chia-Wei Chou, Whitney Pickens, Vicente Más and Jason S. McLellan ()
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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

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28931-3

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