Cleavage targets and the D-arginine-based inhibitors of the West Nile virus NS3 processing proteinase

Sergey A. Shiryaev, Boris I. Ratnikov, Alexei V. Chekanov, Sergey Sikora, Dmitri Rozanov, Adam Godzik, Jun Wang, Jeffrey W. Smith, Ziwei Huang, Iris Lindberg, Melanie A. Samuel, Michael S. Diamond, Alex Y. Strongin

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Abstract

Mosquito-borne WNV (West Nile virus) is an emerging global threat. The NS3 proteinase, which is essential for the proteolytic processing of the viral polyprotein precursor, is a promising drug target. We have isolated and biochemically characterized the recombinant, highly active NS3 proteinase. We have determined that the NS3 proteinase functions in a manner that is distantly similar to furin in cleaving the peptide and protein substrates. We determined that aprotinin and D-arginine-based 9-12-mer peptides are potent inhibitors of WNV NS3 with Ki values of 26 nM and 1 nM respectively. Consistent with the essential role of NS3 activity in the life cycle of WNV and with the sensitivity of NS3 activity to the D-arginine-based peptides, we showed that nona-D-Arg-NH2 reduced WNV infection in primary neurons. We have also shown that myelin basic protein, a deficiency of which is linked to neurological abnormalities of the brain, is sensitive to NS3 proteolysis in vitro and therefore this protein represents a convenient test substrate for the studies of NS3. A three-dimensional model of WNV NS3 that we created may provide a structural guidance and a rationale for the subsequent design of fine-tuned inhibitors. Overall, our findings represent a foundation for in-depth mechanistic and structural studies as well as for the design of novel and efficient inhibitors of WNV NS3.

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Shiryaev, S. A., Ratnikov, B. I., Chekanov, A. V., Sikora, S., Rozanov, D., Godzik, A., ... Strongin, A. Y. (2006). Cleavage targets and the D-arginine-based inhibitors of the West Nile virus NS3 processing proteinase. Biochemical Journal, 393(2), 503-511. https://doi.org/10.1042/BJ20051374