Unknown

Dataset Information

0

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


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 K(i) 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.

SUBMITTER: Shiryaev SA 

PROVIDER: S-EPMC1360700 | BioStudies | 2006-01-01

SECONDARY ACCESSION(S): MER00282

REPOSITORIES: biostudies

Similar Datasets

2008-01-01 | S-EPMC2427327 | BioStudies
2007-01-01 | S-EPMC1900165 | BioStudies
2010-01-01 | S-EPMC2958048 | BioStudies
2017-01-01 | S-EPMC5411607 | BioStudies
2007-01-01 | S-EPMC1770841 | BioStudies
2017-01-01 | S-EPMC6445162 | BioStudies
2019-01-01 | S-EPMC6211275 | BioStudies
2008-01-01 | S-EPMC2648976 | BioStudies
2011-01-01 | S-EPMC3095516 | BioStudies
2007-01-01 | S-EPMC2206648 | BioStudies