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

Research output: Contribution to journalArticle

78 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)503-511
Number of pages9
JournalBiochemical Journal
Volume393
Issue number2
DOIs
StatePublished - Jan 15 2006
Externally publishedYes

Fingerprint

West Nile virus
Viruses
Arginine
Peptide Hydrolases
Processing
Peptides
Furin
Proteolysis
Polyproteins
Protein Deficiency
Aprotinin
Myelin Basic Protein
Virus Diseases
Substrates
Life Cycle Stages
Culicidae
Neurons
Life cycle
Brain
Proteins

Keywords

  • Dengue virus
  • Flavivirus
  • Furin
  • Peptide inhibitor
  • Proteinase
  • West Nile virus

ASJC Scopus subject areas

  • Biochemistry

Cite this

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

Cleavage targets and the D-arginine-based inhibitors of the West Nile virus NS3 processing proteinase. / Shiryaev, Sergey A.; Ratnikov, Boris I.; Chekanov, Alexei V.; Sikora, Sergey; Rozanov, Dmitri; Godzik, Adam; Wang, Jun; Smith, Jeffrey W.; Huang, Ziwei; Lindberg, Iris; Samuel, Melanie A.; Diamond, Michael S.; Strongin, Alex Y.

In: Biochemical Journal, Vol. 393, No. 2, 15.01.2006, p. 503-511.

Research output: Contribution to journalArticle

Shiryaev, SA, Ratnikov, BI, Chekanov, AV, Sikora, S, Rozanov, D, Godzik, A, Wang, J, Smith, JW, Huang, Z, Lindberg, I, Samuel, MA, Diamond, MS & Strongin, AY 2006, 'Cleavage targets and the D-arginine-based inhibitors of the West Nile virus NS3 processing proteinase', Biochemical Journal, vol. 393, no. 2, pp. 503-511. https://doi.org/10.1042/BJ20051374
Shiryaev, Sergey A. ; Ratnikov, Boris I. ; Chekanov, Alexei V. ; Sikora, Sergey ; Rozanov, Dmitri ; Godzik, Adam ; Wang, Jun ; Smith, Jeffrey W. ; Huang, Ziwei ; Lindberg, Iris ; Samuel, Melanie A. ; Diamond, Michael S. ; Strongin, Alex Y. / Cleavage targets and the D-arginine-based inhibitors of the West Nile virus NS3 processing proteinase. In: Biochemical Journal. 2006 ; Vol. 393, No. 2. pp. 503-511.
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