Small-molecule quinolinol inhibitor identified provides protection against BoNT/A in mice

• Published in: PloS one Vol. 7; no. 10; p. e47110
• Main Authors: Singh, Padma, Singh, Manglesh Kumar, Chaudhary, Dilip, Chauhan, Vinita, Bharadwaj, Pranay, Pandey, Apurva, Upadhyay, Nisha, Dhaked, Ram Kumar
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 11.10.2012; Public Library of Science (PLoS)
• Subjects: Aminoquinolines - pharmacology; Analogs; Animals; Biocompatibility; Biology; Biotechnology; Botulinum toxin; Botulinum toxin type A; Botulinum Toxins, Type A - antagonists & inhibitors; Botulinum Toxins, Type A - chemistry; Botulinum Toxins, Type A - toxicity; Botulism; Botulism - drug therapy; Brain; Breast cancer; Cancer therapies; Care and treatment; Chains; Clostridium botulinum; Computer Simulation; Drug Evaluation, Preclinical - methods; Drug therapy; Endopeptidase; Endopeptidases; Etiology; Female; Flexibility; Food contamination; Health aspects; Hydroxyquinolines - pharmacology; Immunization; Immunotherapy; Inhibition; Inhibitors; Inhibitory Concentration 50; Intoxication; Medicine; Mice; Mice, Inbred BALB C; Molecular Docking Simulation; Neurotoxins; Pharmacology; Prophylaxis; Proteins; R&D; Research & development; Small Molecule Libraries; Synaptosomes; Synaptosomes - drug effects; Synaptosomes - metabolism; Toxic substances; Toxicity; Toxins; Water-borne diseases; Waterborne diseases; Zinc; India
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0047110

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).