Rational design of novel antimicrobials: blocking purine salvage in a parasitic protozoan

Biochemistry
J R SomozaC C Wang

Abstract

All parasitic protozoa obtain purine nucleotides solely by salvaging purine bases and/or nucleosides from their host. This observation suggests that inhibiting purine salvage may be a good way of killing these organisms. To explore this idea, we attempted to block the purine salvage pathway of the parasitic protozoan Tritrichomonas foetus. T. foetus is a good organism to study because its purine salvage depends primarily on a single enzyme, hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRTase), and could provide a good model for rational drug design through specific enzyme inhibition. Guided by the crystal structure of T. foetus HGXPRTase, we used structure-based drug design to identify several non-purine compounds that inhibited this enzyme without any detectable effect on human HGPRTase. One of these compounds, 4-[N-(3, 4-dichlorophenyl)carbamoyl]phthalic anhydride (referred to as TF1), was selected for further characterization. TF1 was shown to be a competitive inhibitor of T. foetus HGXPRTase with respect to both guanine (in the forward reaction; Ki = 13 microM) and GMP (in the reverse reaction; Ki = 10 microM), but showed no effect on the homologous human enzyme at concentrations of up to 1 mM. TF1 inhibited ...Continue Reading

Citations

Apr 29, 2011·Journal of Parasitic Diseases : Official Organ of the Indian Society for Parasitology·Bhavna Chawla, Rentala Madhubala
Nov 27, 1999·Life Sciences·A GhérardiF Peyron
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Sep 3, 2003·Pharmacology & Therapeutics·Mahmoud H el Kouni
Apr 4, 2003·Molecular and Biochemical Parasitology·Narsimha Rao Munagala, Ching C Wang
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Jun 12, 2010·Expert Opinion on Therapeutic Targets·Sunandini ChandraRam A Vishwakarma
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