Toxin Inhibition - Deconvolution Strategies and Essay Screening of Combinatorial Peptide Libraries

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Authors
  1. Lee, W.E.
  2. Chan, N.W.C.
  3. Marenco, A.J.
  4. Moore, G.J.
  5. Moore, D.
  6. Hayden, L.J.
  7. Dickinson Laing, T.
  8. Gregory, M.
  9. Mah, D.C.W.
  10. Hamilton, M.G.
Corporate Authors
Defence R&D Canada - Suffield, Ralston ALTA (CAN);Pepmetics Inc., Victoria BC (CAN);Harvest Research Associates, Hillsboro, Oregon (US);Canada West Biosciences, Calgary ALTA (CAN)
Abstract
Combinatorial peptide libraries offer an expedient source of structurally diverse molecules that could serve as lead compounds in the development of drug therapies to toxins. The libraries have typical structures of X1 – X2 – hinge – X3 – X4, where X1 through X4 are near-equimolar mixtures of twelve α-L-amino acids and hinge = γ-aminobutyric acid. Screening of the libraries for inhibitory activity in assays for botulinum neurotoxins A and B (BoNT/A, BoNT/B) and saxitoxin uncovered potent library subsets. For effective screening of the peptide libraries, improved methods of analysis were sought. We report on development of a capillary electrophoresis laser-induced fluorescence (CE LIF) method for measuring BoNT/A peptidase activity and for screening peptide libraries for inhibitory effects. A second analytical method for quantitation of BoNT/A assays was employed based on fluorescence resonance energy transfer (FRET). The FRET assay is homogeneous phase, i.e., no separation step is required. Thus assay time was reduced and throughput increased. The research described in this report was supported by the Technology Investment Fund of Defence R&D Canada.

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Report Number
DRDC-SUFFIELD-TR-2007-051 — Technical Report
Date of publication
01 Aug 2007
Number of Pages
46
DSTKIM No
CA029834
CANDIS No
528242
Format(s):
CD ROM

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