Structural highlights
FunctionPublication Abstract from PubMedThe 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 degrees 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. Structure-based design of prefusion-stabilized human metapneumovirus fusion proteins.,Hsieh CL, Rush SA, Palomo C, Chou CW, Pickens W, Mas V, McLellan JS Nat Commun. 2022 Mar 14;13(1):1299. doi: 10.1038/s41467-022-28931-3. PMID:35288548[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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