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Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322,1 Department of Chemistry, Emory University, Atlanta, Georgia 303222
Received 7 April 2007/ Accepted 25 May 2007
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.
Published ahead of print on 6 June 2007.
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