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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Research Article|
December 23 2005
Cleavage targets and the D-arginine-based inhibitors of the West Nile virus NS3 processing proteinase
Sergey A. Shiryaev;
Sergey A. Shiryaev
1
*The Burnham Institute, La Jolla, CA 92037, U.S.A.
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Boris I. Ratnikov;
Boris I. Ratnikov
1
*The Burnham Institute, La Jolla, CA 92037, U.S.A.
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Alexei V. Chekanov;
Alexei V. Chekanov
1
*The Burnham Institute, La Jolla, CA 92037, U.S.A.
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Sergey Sikora;
Sergey Sikora
*The Burnham Institute, La Jolla, CA 92037, U.S.A.
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Dmitri V. Rozanov;
Dmitri V. Rozanov
*The Burnham Institute, La Jolla, CA 92037, U.S.A.
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Adam Godzik;
Adam Godzik
*The Burnham Institute, La Jolla, CA 92037, U.S.A.
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Jun Wang;
Jun Wang
*The Burnham Institute, La Jolla, CA 92037, U.S.A.
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Jeffrey W. Smith;
Jeffrey W. Smith
*The Burnham Institute, La Jolla, CA 92037, U.S.A.
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Ziwei Huang;
Ziwei Huang
*The Burnham Institute, La Jolla, CA 92037, U.S.A.
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Iris Lindberg;
Iris Lindberg
†Louisiana State University Health Sciences Center, New Orleans, LA 70112, U.S.A.
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Melanie A. Samuel;
Melanie A. Samuel
‡Departments of Medicine and Molecular Microbiology, Washington University Medical School, St. Louis, MO 63110, U.S.A.
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Michael S. Diamond;
Michael S. Diamond
‡Departments of Medicine and Molecular Microbiology, Washington University Medical School, St. Louis, MO 63110, U.S.A.
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Alex Y. Strongin
Alex Y. Strongin
2
*The Burnham Institute, La Jolla, CA 92037, U.S.A.
2To whom correspondence should be addressed (email strongin@burnham.org).
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Publisher: Portland Press Ltd
Received:
August 22 2005
Revision Received:
September 12 2005
Accepted:
October 17 2005
Accepted Manuscript online:
October 17 2005
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2006
Biochem J (2006) 393 (2): 503–511.
Article history
Received:
August 22 2005
Revision Received:
September 12 2005
Accepted:
October 17 2005
Accepted Manuscript online:
October 17 2005
Connected Content
A commentary has been published:
Unexpected similarity between the cytosolic West Nile virus NS3 and the secretory furin-like serine proteinases
Citation
Sergey A. Shiryaev, Boris I. Ratnikov, Alexei V. Chekanov, Sergey Sikora, Dmitri V. Rozanov, Adam Godzik, Jun Wang, Jeffrey W. Smith, Ziwei Huang, Iris Lindberg, Melanie A. Samuel, Michael S. Diamond, Alex Y. Strongin; Cleavage targets and the D-arginine-based inhibitors of the West Nile virus NS3 processing proteinase. Biochem J 15 January 2006; 393 (2): 503–511. doi: https://doi.org/10.1042/BJ20051374
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