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Phosphonate inhibitors of West Nile virus NS2B/NS3 protease.


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 ?-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.

SUBMITTER: Skorenski M 

PROVIDER: S-EPMC6211275 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Phosphonate inhibitors of West Nile virus NS2B/NS3 protease.

Skoreński Marcin M   Milewska Aleksandra A   Pyrć Krzysztof K   Sieńczyk Marcin M   Oleksyszyn Józef J  

Journal of enzyme inhibition and medicinal chemistry 20191201 1


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  ...[more]

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