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Online ISSN: 1860-7187
January 12, 2013
VIP: Development and Characterization of New Peptidomimetic Inhibitors of the West Nile Virus NS2B-NS3 Protease
M. Zouhir Hammamy, Caroline Haase, Maya Hammami, Rolf Hilgenfeld, Torsten Steinmetzer*
The West Nile virus (WNV) is a mosquito-borne flavivirus, which has spread to various regions of Africa, Asia, North America, and Europe. A small number of infected people, primarily children and the elderly, can develop fatal meningitis or encephalitis. Despite increasing demand, there is currently no available specific treatment for WNV infections or human vaccine.
The WNV RNA genome is translated into a polyprotein that must be processed into structural and nonstructural proteins by cellular host proteases and the viral NS2B-NS3 protease. Therefore, the NS2B-NS3 protease has emerged as a potential and specific target for the treatment of WNV infections. Only a few synthetic inhibitors of the WNV protease are known so far; the most potent analogues contain a nonspecific and reactive arginal warhead, which limits their further development.
A collaborative research effort led by Torsten Steinmetzer at the University of Marburg (Germany) has provided a new series of potent substrate analogue inhibitors of the WNV protease containing an inert decarboxylated arginine mimetic in place of the reactive arginal group. Selectivity measurements revealed an excellent specificity profile for these inhibitors, which possess negligible affinity against several tested trypsin-like serine proteases. For one of the most potent inhibitors, a crystal structure in complex with the WNV protease was solved by the research group of Rolf Hilgenfeld at the University of Lübeck (Germany). The inhibitor adopts a horseshoe-like conformation, most likely due to intramolecular hydrophobic contacts, which are further stabilized by a strong intramolecular hydrogen bond. These inhibitors are stable, chemically readily accessible, and may serve as suitable lead structures for further development.
Received October 26, 2012; published online January 10, 2013, DOI: 10.1002/cmdc.201200497.