Peptides as Therapeutic Agents for Dengue Virus

Chew, Miaw-Fang; Poh, Keat-Seong; Poh, Chit-Laa

In a previous study, Schuller et al. (2011) synthesized a series of tripeptide aldehyde inhibitors whereby four of them had the IC50 values in the range between ~6.7 and 12.2 µM against the DENV-2 NS2B-NS3 protease [161] . Among the four tripeptide aldehyde inhibitors, tripeptide 1 (benzoyl-n-Lys-Arg-Arg-H) and tripeptide 2 (phenylacetyl-Lys-Arg-Arg-H) were reported to have the most potential as anti-DENV candidates with IC50 of 9.5 µM and 6.7 µM, respectively [162] . Further investigation of the tripeptide1 revealed that it bound covalently to the DENV-3 NS2B-NS3 protease and resulted in the formation of a closed conformation of the NS2B-NS3 protease in which the hydrophilic β-hairpin region of NS2B would wrap around the NS3 core [163] . Structural analysis of this protease-peptide complex further revealed a pocket located on the NS2B-NS3 protease which could act as a new antiviral target for drug development [163] . Another protease inhibitor, aprotinin, a large polypeptide [also known as bovine pancreatic trypsin inhibitor (BPTI)] was hypothesized to form multiple interactions with the NS2B-NS3 protease and gained its inhibitory activity from the steric hindrance of the active site [163] . In contrast to tripeptide 1 which required the interactions with NS2B, no direct binding was observed between aprotinin and NS2B [163] .