AI Article Synopsis
- Botulinum neurotoxins (BoNTs) are extremely toxic substances that can cause botulism, and there are currently no approved treatments for BoNT intoxication, making it crucial to develop small-molecule inhibitors.
- Researchers are screening compounds from chemical libraries and found several quinolinol derivatives that effectively inhibit the light chain of botulinum neurotoxin type A in vitro, demonstrating promising results.
- One compound, NSC 84087, stands out as a potent and non-toxic inhibitor, showing potential for future therapeutic applications against botulism.
Article Abstract
Botulinum neurotoxins (BoNTs), etiological agents of the life threatening neuroparalytic disease botulism, are the most toxic substances currently known. The potential for the use as bioweapon makes the development of small-molecule inhibitor against these deadly toxins is a top priority. Currently, there are no approved pharmacological treatments for BoNT intoxication. Although an effective vaccine/immunotherapy is available for immuno-prophylaxis but this cannot reverse the effects of toxin inside neurons. A small-molecule pharmacological intervention, especially one that would be effective against the light chain protease, would be highly desirable. Similarity search was carried out from ChemBridge and NSC libraries to the hit (7-(phenyl(8-quinolinylamino)methyl)-8-quinolinol; NSC 84096) to mine its analogs. Several hits obtained were screened for in silico inhibition using AutoDock 4.1 and 19 new molecules selected based on binding energy and Ki. Among these, eleven quinolinol derivatives potently inhibited in vitro endopeptidase activity of botulinum neurotoxin type A light chain (rBoNT/A-LC) on synaptosomes isolated from rat brain which simulate the in vivo system. Five of these inhibitor molecules exhibited IC(50) values ranging from 3.0 nM to 10.0 µM. NSC 84087 is the most potent inhibitor reported so far, found to be a promising lead for therapeutic development, as it exhibits no toxicity, and is able to protect animals from pre and post challenge of botulinum neurotoxin type A (BoNT/A).
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|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3469547 | PMC |
| http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0047110 | PLOS |
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