Combinatorial Strategies and High Throughput Screening in Drug Discovery Targeted to the Channel of Botulinum Neurotoxin
Abstract
The ultimate goal of this program is to discover selective and potent drugs targeted to prevent or relieve the neurotoxic actions of botulinum neurotoxin (BoNT) A. A major goal of this program is the identification of open channel blockers as a single class of drugs that would be effective against all BoNT isoforms. The major focus thus far has been the implementation of a reliable and robust high-throughput screen for blockers specific for BoNT. This facet of the program involves the use of the VIPR(Trademark) Voltage/Ion Probe Reader, a proven strategy for high-throughput screening, using nerve growth factor-differentiated pheochromocytoma PC12 cells in which BoNTA forms channels with similar properties to those previously characterized in lipid bilayers. The fidelity of the assay relies on fluorescence measurements of membrane potential changes as an index of open BoNT channels and increased cation conductance. The immediate task is to select mixtures from synthetic combinatorial libraries with high blocking activity to deconvolute and identify the most potent compounds. We consider the BoNT channel as a validated target for intervention aimed to inhibit the translocation of the light chain into the cytosol and therefore to attenuate the BoNT neurotoxicity.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2003
- Accession Number
- ADA419148
Entities
People
- Mauricio Montal
Organizations
- University of California, San Diego