2026-04-29T07:24:22Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/144672025-06-03T18:10:27Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19609
Repisalud
author
Hsieh, Ching-Lin
author
Rush, Scott A
author
Palomo-Sanz, Concepcion
author
Chou, Chia-Wei
author
Pickens, Whitney
author
Mas-Lloret, Vicente
author
McLellan, Jason S
funder
University of Chicago (Estados Unidos)
funder
Welch Foundation
funder
United States Department of Energy
2022-05-24T06:51:58Z
2022-05-24T06:51:58Z
2022-03-14
Nat Commun. 2022 Mar 14;13(1):1299.
http://hdl.handle.net/20.500.12105/14467
35288548
10.1038/s41467-022-28931-3
2041-1723
Nature Communications
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.
eng
Protein vaccines
Virology
X-ray crystallography
Structure-based design of prefusion-stabilized human metapneumovirus fusion proteins
research article
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