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

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

doi:10.1038/s41467-022-28931-3

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

Journal Article · Mon Mar 14 00:00:00 EDT 2022 · Nature Communications

DOI:https://doi.org/10.1038/s41467-022-28931-3· OSTI ID:1863050

^[1]; ^[1]; Palomo, Concepcion ^[2]; Chou, Chia-Wei ^[1]; ^[1]; Más, Vicente ^[2]; ^[1]

Univ. of Texas, Austin, TX (United States)
National Center for Microbiology (CNM), Madrid (Spain)

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 15mg/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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: Cancer Prevention and Research Institute of Texas; USDOE Office of Science (SC), Biological and Environmental Research (BER); Welch Foundation

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1863050

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 13; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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