Small-molecule quinolinol inhibitor identified provides protection against BoNT/A in mice.
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).
Biotechnology Division, Defence Research and Development Establishment, Gwalior, Madhya Pradesh, India.
Padma
P
Singh
Manglesh Kumar
MK
Singh
Dilip
D
Chaudhary
Vinita
V
Chauhan
Pranay
P
Bharadwaj
Apurva
A
Pandey
Nisha
N
Upadhyay
Ram Kumar
RK
Dhaked
D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000633:toxicity*; D001906:Botulism / Q000188:drug therapy; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006912:Hydroxyquinolines / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D051379:Mice; D008807:Mice, Inbred BALB C; D062105:Molecular Docking Simulation; D054852:Small Molecule Libraries; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
C545211:7-(phenyl(8-quinolinylamino)methyl)-8-quinolinol; D000634:Aminoquinolines; D006912:Hydroxyquinolines; C580747:NSC 84087; D054852:Small Molecule Libraries; D019274:Botulinum Toxins, Type A