Publication: Design and evaluation of substrate-based octapeptide and non substrate-based tetrapeptide inhibitors of dengue virus NS2B-NS3 proteases
Issued Date
2013-05-17
Resource Type
ISSN
10902104
0006291X
0006291X
Other identifier(s)
2-s2.0-84878175594
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Mahidol University
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SCOPUS
Bibliographic Citation
Biochemical and Biophysical Research Communications. Vol.434, No.4 (2013), 767-772
Suggested Citation
Peteris Prusis, Muhammad Junaid, Ramona Petrovska, Sviatlana Yahorava, Aleh Yahorau, Gerd Katzenmeier, Maris Lapins, Jarl E S Wikberg Design and evaluation of substrate-based octapeptide and non substrate-based tetrapeptide inhibitors of dengue virus NS2B-NS3 proteases. Biochemical and Biophysical Research Communications. Vol.434, No.4 (2013), 767-772. doi:10.1016/j.bbrc.2013.03.139 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/31309
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Title
Design and evaluation of substrate-based octapeptide and non substrate-based tetrapeptide inhibitors of dengue virus NS2B-NS3 proteases
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Abstract
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 (Km) and cleavage rate constants (kcat) 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 Kivalues of 4.2, 4.8, 24.4, and 11.2μM 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-NH2into the X-ray structure of DEN-3 protease. © 2013 The Authors.