Structures of the prefusion form of measles virus fusion protein in complex with inhibitors

Proceedings of the National Academy of Sciences of the United States of America
Takao HashiguchiYusuke Yanagi

Abstract

Measles virus (MeV), a major cause of childhood morbidity and mortality, is highly immunotropic and one of the most contagious pathogens. MeV may establish, albeit rarely, persistent infection in the central nervous system, causing fatal and intractable neurodegenerative diseases such as subacute sclerosing panencephalitis and measles inclusion body encephalitis. Recent studies have suggested that particular substitutions in the MeV fusion (F) protein are involved in the pathogenesis by destabilizing the F protein and endowing it with hyperfusogenicity. Here we show the crystal structures of the prefusion MeV-F alone and in complex with the small compound AS-48 or a fusion inhibitor peptide. Notably, these independently developed inhibitors bind the same hydrophobic pocket located at the region connecting the head and stalk of MeV-F, where a number of substitutions in MeV isolates from neurodegenerative diseases are also localized. Since these inhibitors could suppress membrane fusion mediated by most of the hyperfusogenic MeV-F mutants, the development of more effective inhibitors based on the structures may be warranted to treat MeV-induced neurodegenerative diseases.

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Citations

Nov 7, 2019·Viruses·Marion FerrenCyrille Mathieu
Jan 18, 2020·The Journal of Biological Chemistry·Chanakha K NavaratnarajahRoberto Cattaneo
Feb 6, 2020·Viruses·Kristopher D Azarm, Benhur Lee
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May 20, 2021·Cellular & Molecular Immunology·Cyrille MathieuMatteo Porotto
Jul 2, 2021·Annual Review of Virology·Han-Yuan Liu, Priscilla L Yang

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