Quinolinol and Peptide Inhibitors of Zinc Protease in Botulinum Neurotoxin A: Effects of Zinc Ion and Peptides on Inhibition
ARMY MEDICAL RESEARCH INST OF INFECTIOUS DISEASES FORT DETRICK MD
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Quinolinol derivatives were found to be effective inhibitors of botulinum neurotoxin serotype A BoNT A. Studies of the inhibition and binding of 7-phenyl8-quinolinylaminomethyl-8-quinolinol QAQ to the light chain domain BoNTA LC showed that QAQ is a non-competitive inhibitor for the zinc protease activity. Binding and molecular modeling studies reveal that QAQ binds to a hydrophobic pocket near the active site. Its inhibitor effect does not involve the removal of zinc ion from the light chain. A 24-mer SNAP-25 peptide containing E183 to G206 with Q197C mutation Peptide C binds to BoNTA LC with an unusually slow second order binding rate constant of 76.7 M1 s1. QAQ binds to Zn2-free BoNTA LC with a KD of 0.67 lM and to Peptide CBoNTA LC complex with a KD of 2.33 lM. The insights of the interactions of quinolinols and peptides with the zinc protease of BoNTA should aid in the development of inhibitors of metalloproteases.