Number of the records: 1

Design and Synthesis of Fluorescent Acyclic Nucleoside Phosphonates as Potent Inhibitors of Bacterial Adenylate Cyclases

SYSNO ASEP	0467409
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	Design and Synthesis of Fluorescent Acyclic Nucleoside Phosphonates as Potent Inhibitors of Bacterial Adenylate Cyclases
Author(s)	Břehová, Petra (UOCHB-X)_{RID, ORCID} Šmídková, Markéta (UOCHB-X)_{RID, ORCID} Skácel, Jan (UOCHB-X)_{ORCID, RID} Dračínský, Martin (UOCHB-X)_{RID, ORCID} Mertlíková-Kaiserová, Helena (UOCHB-X)_{RID, ORCID} Velasquez, M. P. S. (US) Watts, V. J. (US) Janeba, Zlatko (UOCHB-X)_{RID, ORCID}
Source Title	ChemMedChem. - : Wiley - ISSN 1860-7179 Roč. 11, č. 22 (2016), s. 2534-2546
Number of pages	13 s.
Language	eng - English
Country	DE - Germany
Keywords	adenylate cyclase toxin ; acyclic nucleoside phosphonates ; anthranilic acid
Subject RIV	CC - Organic Chemistry
R&D Projects	VG20102015046 GA MV - Ministry of Interior (MV)
	LO1302 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
Institutional support	UOCHB-X - RVO:61388963
UT WOS	000388507100008
EID SCOPUS	84995953618
DOI	10.1002/cmdc.201600439
Annotation	Bordetella pertussis adenylate cyclase toxin (ACT) and Bacillus anthracis edema factor (EF) are key virulence factors with adenylate cyclase (AC) activity that substantially contribute to the pathogenesis of whooping cough and anthrax, respectively. There is an urgent need to develop potent and selective inhibitors of bacterial ACs with prospects for the development of potential antibacterial therapeutics and to study their molecular interactions with the target enzymes. Novel fluorescent 5-chloroanthraniloyl-substituted acyclic nucleoside phosphonates (Cl-ANT-ANPs) were designed and synthesized in the form of their diphosphates (Cl-ANT-ANPpp) as competitive ACT and EF inhibitors with sub-micromolar potency (IC50 values: 11-622nm). Fluorescence experiments indicated that Cl-ANT-ANPpp analogues bind to the ACT active site, and docking studies suggested that the Cl-ANT group interacts with Phe306 and Leu60. Interestingly, the increase in direct fluorescence with Cl-ANT-ANPpp having an ester linker was strictly calmodulin (CaM)-dependent, whereas Cl-ANT-ANPpp analogues with an amide linker, upon binding to ACT, increased the fluorescence even in the absence of CaM. Such a dependence of binding on structural modification could be exploited in the future design of potent inhibitors of bacterial ACs. Furthermore, one Cl-ANT-ANP in the form of a bisamidate prodrug was able to inhibit B.pertussis ACT activity in macrophage cells with IC50=12m.
Workplace	Institute of Organic Chemistry and Biochemistry
Contact	asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434
Year of Publishing	2017

Number of the records: 1