Ciprofloxacin is an inhibitor of the Mcm2-7 replicative helicase

Most currently available small molecule inhibitors of DNA replication lack enzymatic specificity, resulting in deleterious side effects during use in cancer chemotherapy and limited experimental usefulness as mechanistic tools to study DNA replication. Towards development of targeted replication inh...

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Main Authors:	Simon, Nicholas, Bochman, Matthew L., Seguin, Sandlin, Brodsky, Jeffrey L., Seibel, William L., Schwacha, Anthony
Format:	Online
Language:	English
Published:	Portland Press Ltd. 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791872/

id	pubmed-3791872
recordtype	oai_dc
spelling	pubmed-37918722013-10-07 Ciprofloxacin is an inhibitor of the Mcm2-7 replicative helicase Simon, Nicholas Bochman, Matthew L. Seguin, Sandlin Brodsky, Jeffrey L. Seibel, William L. Schwacha, Anthony Original Paper Most currently available small molecule inhibitors of DNA replication lack enzymatic specificity, resulting in deleterious side effects during use in cancer chemotherapy and limited experimental usefulness as mechanistic tools to study DNA replication. Towards development of targeted replication inhibitors, we have focused on Mcm2-7 (minichromosome maintenance protein 2–7), a highly conserved helicase and key regulatory component of eukaryotic DNA replication. Unexpectedly we found that the fluoroquinolone antibiotic ciprofloxacin preferentially inhibits Mcm2-7. Ciprofloxacin blocks the DNA helicase activity of Mcm2-7 at concentrations that have little effect on other tested helicases and prevents the proliferation of both yeast and human cells at concentrations similar to those that inhibit DNA unwinding. Moreover, a previously characterized mcm mutant (mcm4chaos3) exhibits increased ciprofloxacin resistance. To identify more potent Mcm2-7 inhibitors, we screened molecules that are structurally related to ciprofloxacin and identified several that compromise the Mcm2-7 helicase activity at lower concentrations. Our results indicate that ciprofloxacin targets Mcm2-7 in vitro, and support the feasibility of developing specific quinolone-based inhibitors of Mcm2-7 for therapeutic and experimental applications. Portland Press Ltd. 2013-10-07 /pmc/articles/PMC3791872/ /pubmed/24001138 http://dx.doi.org/10.1042/BSR20130083 Text en © 2013 The Author(s) http://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (CC-BY) (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Simon, Nicholas Bochman, Matthew L. Seguin, Sandlin Brodsky, Jeffrey L. Seibel, William L. Schwacha, Anthony
spellingShingle	Simon, Nicholas Bochman, Matthew L. Seguin, Sandlin Brodsky, Jeffrey L. Seibel, William L. Schwacha, Anthony Ciprofloxacin is an inhibitor of the Mcm2-7 replicative helicase
author_facet	Simon, Nicholas Bochman, Matthew L. Seguin, Sandlin Brodsky, Jeffrey L. Seibel, William L. Schwacha, Anthony
author_sort	Simon, Nicholas
title	Ciprofloxacin is an inhibitor of the Mcm2-7 replicative helicase
title_short	Ciprofloxacin is an inhibitor of the Mcm2-7 replicative helicase
title_full	Ciprofloxacin is an inhibitor of the Mcm2-7 replicative helicase
title_fullStr	Ciprofloxacin is an inhibitor of the Mcm2-7 replicative helicase
title_full_unstemmed	Ciprofloxacin is an inhibitor of the Mcm2-7 replicative helicase
title_sort	ciprofloxacin is an inhibitor of the mcm2-7 replicative helicase
description	Most currently available small molecule inhibitors of DNA replication lack enzymatic specificity, resulting in deleterious side effects during use in cancer chemotherapy and limited experimental usefulness as mechanistic tools to study DNA replication. Towards development of targeted replication inhibitors, we have focused on Mcm2-7 (minichromosome maintenance protein 2–7), a highly conserved helicase and key regulatory component of eukaryotic DNA replication. Unexpectedly we found that the fluoroquinolone antibiotic ciprofloxacin preferentially inhibits Mcm2-7. Ciprofloxacin blocks the DNA helicase activity of Mcm2-7 at concentrations that have little effect on other tested helicases and prevents the proliferation of both yeast and human cells at concentrations similar to those that inhibit DNA unwinding. Moreover, a previously characterized mcm mutant (mcm4chaos3) exhibits increased ciprofloxacin resistance. To identify more potent Mcm2-7 inhibitors, we screened molecules that are structurally related to ciprofloxacin and identified several that compromise the Mcm2-7 helicase activity at lower concentrations. Our results indicate that ciprofloxacin targets Mcm2-7 in vitro, and support the feasibility of developing specific quinolone-based inhibitors of Mcm2-7 for therapeutic and experimental applications.
publisher	Portland Press Ltd.
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791872/
_version_	1612016728525504512

Ciprofloxacin is an inhibitor of the Mcm2-7 replicative helicase

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