Exploring new inhibitors of Plasmodium falciparum purine nucleoside phosphorylase.
Plasmodium falciparum purine nucleoside phosphorylase (PfPNP) has a central role in purine salvage and inhibitors of the enzyme have been shown to have antiplasmodial activity. The enzyme preferentially uses inosine as substrate (K(m)=5 μM, k(cat)/K(m)=7.4×10(4) M(-1) s(-1)), but can also use uridine, albeit less efficiently (K(m)=85 μM, k(cat)/K(m)=306 M(-1) s(-1)). In an effort to identify new PfPNP inhibitors, two series of compounds were prepared. Series 1 was based on known human uridine phosphorylase inhibitors whilst series 2 was uracil equivalents of purine-based PNP transition state inhibitors. These two series of compounds were assayed for inhibition of both PfPNP activity and growth of P. falciparum. The transition state analogues were found to be moderate inhibitors of PfPNP (most potent compound, K(i)=6 μM).
Cui
Huaqing
H
Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Avda. del Conocimiento s/n, 18100-Armilla, Granada, Spain.
Ruda
Gian Filippo
GF
Carrero-Lérida
Juana
J
Ruiz-Pérez
Luis M
LM
Gilbert
Ian H
IH
González-Pacanowska
Dolores
D
D000818:Animals; D002853:Chromatography, Liquid; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000201:enzymology*; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D021241:Spectrometry, Mass, Electrospray Ionization
D004791:Enzyme Inhibitors; D011683:Purine-Nucleoside Phosphorylase