Abstract
West Nile virus (WNV) is a member of the flavivirus genus belonging to the Flaviviridae family. The viral serine protease NS2B/NS3 has been considered an attractive target for the development of anti-WNV agents. Although several NS2B/NS3 protease inhibitors have been described so far, most of them are reversible inhibitors. Herein, we present a series of α-aminoalkylphosphonate diphenyl esters and their peptidyl derivatives as potent inhibitors of the NS2B/NS3 protease. The most potent inhibitor identified was Cbz-Lys-Arg-(4-GuPhe)P(OPh)2 displaying Ki and k2/Ki values of 0.4 µM and 28 265 M−1s−1, respectively, with no significant inhibition of trypsin, cathepsin G, and HAT protease.
Highlights
The West Nile virus (WNV) belongs to the flavivirus genus (Flaviviridae family) and is a mosquito-borne human pathogen of global occurrence
An interesting reversible inhibitor of NS2B/NS3 was described by Behnam et al.1 5 compound 5 containing a benzyloxyphenylglycine residue at P1 position showed a significant reduction of Dengue and WNV titres in cell-based assays of virus replication (EC5 0 = 15.5 mM)
We present a series of lysine, arginine, and peptidyl diphenylphosphonate derivatives which could be considered as starting templates for further structure optimisation studies as NS2B/NS3 protease inhibitors
Summary
Marcin Skoreńskia, Aleksandra Milewskab,c, Krzysztof Pyrcbc, Marcin Sieńczyka and Józef Oleksyszyna aFaculty of Chemistry, Division of Medicinal Chemistry and Microbiology, Wroclaw University of Science and Technology, Wroclaw, Poland; bFaculty of Biochemistry, Biophysics and Biotechnology, Microbiology Department, Jagiellonian University, Krakow, Poland; cLaboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland
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