Počet záznamů: 1
Design of Plasmodium vivax Hypoxanthine-Guanine Phosphoribosyltransferase Inhibitors as Potential Antimalarial Therapeutics
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SYSNO ASEP 0489497 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Design of Plasmodium vivax Hypoxanthine-Guanine Phosphoribosyltransferase Inhibitors as Potential Antimalarial Therapeutics Tvůrce(i) Keough, D. T. (AU)
Rejman, Dominik (UOCHB-X) RID, ORCID
Pohl, Radek (UOCHB-X) RID, ORCID
Zborníková, Eva (UOCHB-X) RID, ORCID
Hocková, Dana (UOCHB-X) RID, ORCID
Croll, T. (AU)
Edstein, M. D. (AU)
Birrell, G. W. (AU)
Chavchich, M. (AU)
Naesens, L. M. J. (BE)
Pierens, G. K. (AU)
Brereton, I. M. (AU)
Guddat, L. W. (AU)Zdroj.dok. ACS Chemical Biology. - : American Chemical Society - ISSN 1554-8929
Roč. 13, č. 1 (2018), s. 82-90Poč.str. 9 s. Jazyk dok. eng - angličtina Země vyd. US - Spojené státy americké Klíč. slova plasmodium vivax ; inhibitor ; pyrrolidine nucleotide bisphosphonate ; HXGPRT Vědní obor RIV CC - Organická chemie Obor OECD Organic chemistry CEP GA16-06049S GA ČR - Grantová agentura ČR GA15-11711S GA ČR - Grantová agentura ČR Institucionální podpora UOCHB-X - RVO:61388963 UT WOS 000423252600009 EID SCOPUS 85040864284 DOI 10.1021/acschembio.7b00916 Anotace Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) are the foremost causative agents of malaria. Due to the development of resistance to current antimalarial medications, new drugs for this parasitic disease need to be discovered. The activity of hypoxanthine-guanine-[xanthine]phosphoribosyltransferase, HG[X]PRT, is reported to be essential for the growth of both of these parasites, making it an excellent target for antimalarial drug discovery. Here, we have used rational structure-based methods to design an inhibitor, [3R,4R]-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine, of PvHGPRT and PfHGXPRT that has K-i values of 8 and 7 nM, respectively, for these two enzymes. The crystal structure of PvHGPRT in complex with this compound has been determined to 2.85 angstrom resolution. The corresponding complex with human HGPRT was also obtained to allow a direct comparison of the binding modes of this compound with the two enzymes. The tetra-(ethyl L-phenylalanine) tetraamide prodrug of this compound was synthesized, and it has an IC50 of 11.7 +/- 3.2 mu M against Pf lines grown in culture and a CC50 in human A549 cell lines of 102 +/- 11 mu M, thus giving it a similar to 10-fold selectivity index. Pracoviště Ústav organické chemie a biochemie Kontakt asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Rok sběru 2019
Počet záznamů: 1