title: Synthesis and disulfide bond connectivity-activity studies of a kalata B1-inspired cyclopeptide against dengue NS2B-NS3 protease.
abstract: 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 K(i) of 1.39+/-0.35 and 3.03+/-0.75 microM, respectively.
authors.affiliation: Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore.
authors.forename: Yaojun
authors.initials: Y
authors.lastname: Gao
authors.forename: Taian
authors.initials: T
authors.lastname: Cui
authors.forename: Yulin
authors.initials: Y
authors.lastname: Lam
mesh_terms: D000595:Amino Acid Sequence; D047169:Cyclotides / Q000737:chemistry*; D003715:Dengue / Q000188:drug therapy*; D003716:Dengue Virus / Q000201:enzymology*; D004220:Disulfides / Q000737:chemistry; D015195:Drug Design; D008969:Molecular Sequence Data; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D000085242:Viral Proteases
chemical_list: D047169:Cyclotides; D004220:Disulfides; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; C080102:NS2B protein, flavivirus; C091930:kalata B1; C504449:NS3 protease, dengue virus; D000085242:Viral Proteases