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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.
AuthorsYaojun Gao, Taian Cui, Yulin Lam
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 18 Issue 3 Pg. 1331-6 (Feb 2010) ISSN: 1464-3391 [Electronic] England
PMID20042339 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright (c) 2009 Elsevier Ltd. All rights reserved.
Chemical References
  • Cyclotides
  • Disulfides
  • NS2B protein, flavivirus
  • Serine Proteinase Inhibitors
  • Viral Nonstructural Proteins
  • kalata B1
  • NS3 protease, dengue virus
  • Serine Endopeptidases
Topics
  • Amino Acid Sequence
  • Cyclotides (chemistry)
  • Dengue (drug therapy)
  • Dengue Virus (enzymology)
  • Disulfides (chemistry)
  • Drug Design
  • Molecular Sequence Data
  • Serine Endopeptidases (metabolism)
  • Serine Proteinase Inhibitors (chemistry, isolation & purification, pharmacology)
  • Viral Nonstructural Proteins (metabolism)

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