Počet záznamů: 1  

Amidate Prodrugs of 9-[2-(Phosphonomethoxy)Ethyl]Adenine as Inhibitors of Adenylate Cyclase Toxin from Bordetella pertussis

  1. 1.
    0427655 - UOCHB-X 2015 RIV US eng J - Článek v odborném periodiku
    Šmídková, Markéta - Dvořáková, Alexandra - Tloušťová, Eva - Česnek, Michal - Janeba, Zlatko - Mertlíková-Kaiserová, Helena
    Amidate Prodrugs of 9-[2-(Phosphonomethoxy)Ethyl]Adenine as Inhibitors of Adenylate Cyclase Toxin from Bordetella pertussis.
    Antimicrobial Agents and Chemotherapy. Roč. 58, č. 2 (2014), s. 664-671. ISSN 0066-4804
    Grant CEP: GA MV VG20102015046
    Grant ostatní:OPPC(XE) CZ.2.16/3.1.00/24016
    Institucionální podpora: RVO:61388963
    Klíčová slova: Bordetella pertussis * adenylate cyclase toxin * ACT * inhibitors * PMEA * amidate prodrugs
    Kód oboru RIV: CC - Organická chemie
    Impakt faktor: 4.476, rok: 2014

    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.
    Trvalý link: http://hdl.handle.net/11104/0233171