Title: Acyclic nucleoside phosphonates containing a second phosphonate group are potent inhibitors of 6-oxopurine phosphoribosyltransferases and have antimalarial activity
Authors: Keough, Dianne T ×
Spaček, Petr
Hocková, Dana
Tichý, Tomáš
Vrbková, Silvie
Slavětínská, Lenka
Janeba, Zlatko
Naesens, Lieve
Edstein, Michael D
Chavchich, Marina
Wang, Tzu-Hsuan
de Jersey, John
Guddat, Luke W #
Issue Date: Mar-2013
Publisher: ACS Publications
Series Title: Journal of Medicinal Chemistry vol:56 issue:6 pages:2513-2526
Article number: 10.1021/jm301893b
Abstract: Acyclic nucleoside phosphonates (ANPs) that contain a 6-oxopurine base are good inhibitors of the Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) 6-oxopurine phosphoribosyltransferases (PRTs). Chemical modifications based on the crystal structure of 2-(phosphonoethoxy)ethylguanine (PEEG) in complex with human HGPRT have led to the design of new ANPs. These novel compounds contain a second phosphonate group attached to the ANP scaffold. {[(2-[(Guanine-9H-yl)methyl]propane-1,3-diyl)bis(oxy)]bis(methylene)}diphosphonic acid (compound 17) exhibited a Ki value of 30 nM for human HGPRT and 70 nM for Pf HGXPRT. The crystal structure of this compound in complex with human HGPRT shows that it fills or partially fills three critical locations in the active site: the binding sites of the purine base, the 5'-phosphate group, and pyrophosphate. This is the first HG(X)PRT inhibitor that has been able to achieve this result. Prodrugs have been synthesized resulting in IC50 values as low as 3.8 μM for Pf grown in cell culture, up to 25-fold lower compared to the parent compounds.
ISSN: 0022-2623
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Virology and Chemotherapy (Rega Institute)
× corresponding author
# (joint) last author

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