Reversible inhibition of the fusion activity of measles virus F protein by an engineered intersubunit disulfide bridge.
In search of target sites for the development of paramyxovirus inhibitors, we have engineered disulfide bridges to introduce covalent links into the prefusion F protein trimer of measles virus. F-Edm-452C/460C, predicted to bridge head and stalk domains of different F monomers, shows a high degree of proteolytic maturation and surface expression, predominantly as stable, dithiothreitol-sensitive trimers, but no fusion activity. Reduction of disulfide bridges partially restores activity. These findings underscore the importance of reversible intersubunit interactions between the stalk and head domains for F activity. Noncovalent small molecules mimicking this behavior may constitute a potent strategy for preventing paramyxovirus entry.
Lee
Jin K
JK
Division of Infectious Diseases, Department of Pediatrics, Emory University School of Medicine, 520 Children's Center, 2015 Uppergate Drive, Atlanta, GA 30322, USA.
Prussia
Andrew
A
Snyder
James P
JP
Plemper
Richard K
RK
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D019921:Biotinylation; D002522:Chlorocebus aethiops; D003545:Cysteine / Q000737:chemistry / Q000235:genetics; D004220:Disulfides / Q000737:chemistry*; D004229:Dithiothreitol / Q000494:pharmacology; D015195:Drug Design; D008459:Measles virus / Q000737:chemistry* / Q000187:drug effects; D008561:Membrane Fusion / Q000187:drug effects*; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D015202:Protein Engineering; D019809:Streptavidin / Q000737:chemistry; D014709:Vero Cells; D014760:Viral Fusion Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics
D000998:Antiviral Agents; D004220:Disulfides; D014760:Viral Fusion Proteins; D019809:Streptavidin; D003545:Cysteine; D004229:Dithiothreitol