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,...

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Autores principales:	Padma Singh, Manglesh Kumar Singh, Dilip Chaudhary, Vinita Chauhan, Pranay Bharadwaj, Apurva Pandey, Nisha Upadhyay, Ram Kumar Dhaked
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3aa7304962a043a48e0294dc4c1e006e
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spelling	oai:doaj.org-article:3aa7304962a043a48e0294dc4c1e006e2021-11-18T08:12:21ZSmall-molecule quinolinol inhibitor identified provides protection against BoNT/A in mice.1932-620310.1371/journal.pone.0047110https://doaj.org/article/3aa7304962a043a48e0294dc4c1e006e2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23071727/?tool=EBIhttps://doaj.org/toc/1932-6203Botulinum 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).Padma SinghManglesh Kumar SinghDilip ChaudharyVinita ChauhanPranay BharadwajApurva PandeyNisha UpadhyayRam Kumar DhakedPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 10, p e47110 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Padma Singh Manglesh Kumar Singh Dilip Chaudhary Vinita Chauhan Pranay Bharadwaj Apurva Pandey Nisha Upadhyay Ram Kumar Dhaked Small-molecule quinolinol inhibitor identified provides protection against BoNT/A in mice.
description	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).
format	article
author	Padma Singh Manglesh Kumar Singh Dilip Chaudhary Vinita Chauhan Pranay Bharadwaj Apurva Pandey Nisha Upadhyay Ram Kumar Dhaked
author_facet	Padma Singh Manglesh Kumar Singh Dilip Chaudhary Vinita Chauhan Pranay Bharadwaj Apurva Pandey Nisha Upadhyay Ram Kumar Dhaked
author_sort	Padma Singh
title	Small-molecule quinolinol inhibitor identified provides protection against BoNT/A in mice.
title_short	Small-molecule quinolinol inhibitor identified provides protection against BoNT/A in mice.
title_full	Small-molecule quinolinol inhibitor identified provides protection against BoNT/A in mice.
title_fullStr	Small-molecule quinolinol inhibitor identified provides protection against BoNT/A in mice.
title_full_unstemmed	Small-molecule quinolinol inhibitor identified provides protection against BoNT/A in mice.
title_sort	small-molecule quinolinol inhibitor identified provides protection against bont/a in mice.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/3aa7304962a043a48e0294dc4c1e006e
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Small-molecule quinolinol inhibitor identified provides protection against BoNT/A in mice.

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