Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/14467
Título
Structure-based design of prefusion-stabilized human metapneumovirus fusion proteins
Autor(es)
Hsieh, Ching-Lin | Rush, Scott A | Palomo-Sanz, Concepcion ISCIII | Chou, Chia-Wei | Pickens, Whitney | Mas-Lloret, Vicente ISCIII | McLellan, Jason S
Fecha de publicación
2022-03-14
Cita
Nat Commun. 2022 Mar 14;13(1):1299.
Idioma
Inglés
Tipo de documento
journal article
Resumen
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.
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