Screening of Mimetic Peptide Inhibitors of Neurotoxins and Fragment Fingerprint Analysis of Neurotoxins by Capillary Electrophoresis

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Authors
  1. Mah, D.C.W.
  2. Song, Y.
  3. Crichton, M.
  4. Wong, J.
  5. McWilliams, M.
  6. Dickinson Laing, T.
  7. Jemere, A.
Corporate Authors
Defence Research and Development Canada, Suffield Research Centre, Ralston AB (CAN);Canada West Biosciences Inc, Camrose Alta (CAN)
Abstract
Botulinum neurotoxins (BoNTs) are the most potent of known toxins and are listed as biodefense category A agents. Currently, the only therapy for BoNT intoxication includes experimental preventive antibodies and long-term supportive care. Therefore, there is an urgent need to identify and develop inhibitors that will serve as both prophylactic agents and post-exposure “rescue” therapeutics. In this project, we developed fluorescence resonance energy transfer (FRET) and cell viability assay to identify small molecules and peptides that inhibit the metalloprotease activity of BoNT/A light chain. In this report we employed FRET assay to identify and characterize small chemical inhibitors of botulinum neurotoxin A as potential therapeutic drugs for botulism. Six compounds that significantly inhibited the BoNT/A protease activity were selected for further inhibition studies in rat cortical neurons and hemidiaphragm assay. The reduced toxicity and high potency demonstrated by these six compounds at the biochemical, cellular and tissue levels are distinctive among the the BoNT/A small-molecule inhibitors reported thus far.
Keywords
capillary electrophoresis;Botulinum neurotoxin;inhibition;fluorescence resonance energy transfer
Report Number
DRDC-RDDC-2015-C306 — Contract Report
Date of publication
01 Mar 2015
Number of Pages
62
DSTKIM No
CA041823
CANDIS No
802877
Format(s):
Electronic Document(PDF)

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