Synthesis and disulfide bond connectivity–activity studies of a kalata B1-inspired cyclopeptide against dengue NS2B–NS3 protease

Kalata B1 is a plant protein with remarkable thermal, chemical and enzymatic stability. Its potential applications could be centered on the possibility of using its cyclic structure and cystine knot motif as a scaffold for the design of stable pharmaceuticals. To discover potent dengue NS2B–NS3 protease inhibitors, we have prepared various kalata B1 analogues by varying the amino acid sequence. Mass spectrometric and biochemical investigations of these analogues revealed a cyclopeptide whose two fully oxidized forms are substrate-competitive inhibitors of the dengue viral NS2B–NS3 protease. Both oxidized forms showed potent inhibition with Ki of 1.39 ± 0.35 and 3.03 ± 0.75 μM, respectively.

Two isomers of an oxidized kalata B1 analogue were found to possess potent inhibition against dengue NS2B–NS3 protease. This reveals the importance of disulfide bond connectivity in substrate-competitive inhibitory activity.Figure optionsDownload as PowerPoint slide