Počet záznamů: 1

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

SYSNO ASEP	0467409
Druh ASEP	J - Článek v odborném periodiku
Zařazení RIV	J - Článek v odborném periodiku
Poddruh J	Článek ve WOS
Název	Design and Synthesis of Fluorescent Acyclic Nucleoside Phosphonates as Potent Inhibitors of Bacterial Adenylate Cyclases
Tvůrce(i)	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}
Zdroj.dok.	ChemMedChem. - : Wiley - ISSN 1860-7179 Roč. 11, č. 22 (2016), s. 2534-2546
Poč.str.	13 s.
Jazyk dok.	eng - angličtina
Země vyd.	DE - Německo
Klíč. slova	adenylate cyclase toxin ; acyclic nucleoside phosphonates ; anthranilic acid
Vědní obor RIV	CC - Organická chemie
CEP	VG20102015046 GA MV - Ministerstvo vnitra
	LO1302 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy
Institucionální podpora	UOCHB-X - RVO:61388963
UT WOS	000388507100008
EID SCOPUS	84995953618
DOI	10.1002/cmdc.201600439
Anotace	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.
Pracoviště	Ústav organické chemie a biochemie
Kontakt	asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434
Rok sběru	2017

Počet záznamů: 1