Design and evaluation of substrate-based octapeptide and non substrate-based tetrapeptide inhibitors of dengue virus NS2B-NS3 proteases
2013 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 434, no 4, 767-772 p.Article in journal (Refereed) Published
A series of 45 peptide inhibitors was designed, synthesized, and evaluated against the NS2B-NS3 proteases of the four subtypes of dengue virus, DEN-1-4. The design was based on proteochemometric models for Michaelis (K-m) and cleavage rate constants (k(cat)) of protease substrates. This led first to octapeptides showing submicromolar or low micromolar inhibitory activities on the four proteases. Stepwise removal of cationic substrate non-prime side residues and variations in the prime side sequence resulted finally in an uncharged tetrapeptide, WYCW-NH2, with inhibitory K-i values of 4.2, 4.8, 24.4, and 11.2 mu M for the DEN-1-4 proteases, respectively. Analysis of the inhibition data by proteochemometric modeling suggested the possibility for different binding poses of the shortened peptides compared to the octapeptides, which was supported by results of docking of WYCW-NH2 into the X-ray structure of DEN-3 protease.
Place, publisher, year, edition, pages
2013. Vol. 434, no 4, 767-772 p.
Dengue virus, NS2B-NS3 protease, D-optimal design, Substrate-based, Non-substrate-based, Tetrapeptide inhibitor
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-203557DOI: 10.1016/j.bbrc.2013.03.139ISI: 000320213200012OAI: oai:DiVA.org:uu-203557DiVA: diva2:636948