Development of Targeted Therapeutic Agents for Botulism
Abstract
The neuroparalytic symptoms of human botulism, resulting from inhibition of acetylcholine release by type A botulinum neurotoxin (BoNTIA), are life threatening and last for up to 2 years. Thus, development of a fast and effective treatment for the forces exposed to this threat warrants the highest priority. Initial experiments focussed on developing an avid inhibitor of the BoNTIA protease that cleaves SNAP-25 - a SNARE essential for transmitter release. The inhibitors prepared were toxin-resistant mutants of the full-length substrate that retained ability to mediate exocytosis. This vital advance created a means of overcoming the poisoning by transfecting cultured neuroendocrine cells with these SNAP-25 genes. Importantly, the constructs encoding several non-cleavable SNAP-25s rescued exocytosis in BoNTlA-blocked cells, providing an innovative, efficient and rapid therapy for botulism which can be adopted for humans. Moreover, the observed inability of wild-type SNAP-25 to counteract the toxin's action, even at 3 weeks after intoxication, revealed the amazing longevity of type A protease.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2001
- Accession Number
- ADB270793
Entities
People
- Nadiem Mohammed
- Oliver J. Dolly
- Patrick G. Foran
Organizations
- University of London