Počet záznamů: 1
Amidate Prodrugs of 9-[2-(Phosphonomethoxy)Ethyl]Adenine as Inhibitors of Adenylate Cyclase Toxin from Bordetella pertussis
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SYSNO ASEP 0427655 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Amidate Prodrugs of 9-[2-(Phosphonomethoxy)Ethyl]Adenine as Inhibitors of Adenylate Cyclase Toxin from Bordetella pertussis Tvůrce(i) Šmídková, Markéta (UOCHB-X) RID, ORCID
Dvořáková, Alexandra (UOCHB-X)
Tloušťová, Eva (UOCHB-X) RID, ORCID
Česnek, Michal (UOCHB-X) RID, ORCID
Janeba, Zlatko (UOCHB-X) RID, ORCID
Mertlíková-Kaiserová, Helena (UOCHB-X) RID, ORCIDCelkový počet autorů 6 Zdroj.dok. Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology - ISSN 0066-4804
Roč. 58, č. 2 (2014), s. 664-671Poč.str. 8 s. Jazyk dok. eng - angličtina Země vyd. US - Spojené státy americké Klíč. slova Bordetella pertussis ; adenylate cyclase toxin ; ACT ; inhibitors ; PMEA ; amidate prodrugs Vědní obor RIV CC - Organická chemie CEP VG20102015046 GA MV - Ministerstvo vnitra Institucionální podpora UOCHB-X - RVO:61388963 UT WOS 000330637500005 EID SCOPUS 84893440433 DOI 10.1128/AAC.01685-13 Anotace Adenylate cyclase toxin (ACT) is the key virulence factor of Bordetella pertussis that facilitates its invasion into the mammalian body. 9-[2-(Phosphonomethoxy) ethyl] adenine diphosphate (PMEApp), the active metabolite of the antiviral drug bis(POM) PMEA (adefovir dipivoxil), has been shown to inhibit ACT. The objective of this study was to evaluate six novel amidate prodrugs of PMEA, both phenyloxy phosphonamidates and phosphonodiamidates, for their ability to inhibit ACT activity in the J774A.1 macrophage cell line. The two phenyloxy phosphonamidate prodrugs exhibited greater inhibitory activity (50% inhibitory concentration [IC50] = 22 and 46 nM) than the phosphonodiamidates (IC50 = 84 to 3,960 nM). The inhibitory activity of the prodrugs correlated with their lipophilicity and the degree of their hydrolysis into free PMEA in J774A.1 cells. Although the prodrugs did not inhibit ACT as effectively as bis(POM) PMEA (IC50 = 6 nM), they were significantly less cytotoxic. Moreover, they all reduced apoptotic effects of ACT and prevented an ACT-induced elevation of intracellular [Ca2+](i). The amidate prodrugs were less susceptible to degradation in Caco-2 cells compared to bis(POM) PMEA, while they exerted good transepithelial permeability in this assay. As a consequence, a large amount of intact amidate prodrug is expected to be available to target macrophages in vivo. This feature makes nontoxic amidate prodrugs attractive candidates for further investigation as novel antimicrobial agents. 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 2015
Počet záznamů: 1