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Publication Abstract from PubMed

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-(phosphonopropion yl)pyrrolidine, of PvHGPRT and PfHGXPRT that has Ki 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 A 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 muM against Pf lines grown in culture and a CC50 in human A549 cell lines of 102 +/- 11 muM, thus giving it a approximately 10-fold selectivity index.

Design of Plasmodium vivax Hypoxanthine-Guanine Phosphoribosyltransferase Inhibitors as Potential Antimalarial Therapeutics.,Keough DT, Rejman D, Pohl R, Zbornikova E, Hockova D, Croll T, Edstein MD, Birrell GW, Chavchich M, Naesens LMJ, Pierens GK, Brereton IM, Guddat LW ACS Chem Biol. 2017 Dec 5. doi: 10.1021/acschembio.7b00916. PMID:29161011^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.