Email the author Thianthrene is a novel inhibitor of Leishmania donovani pteridine reductase 1 (PTR1)
Abstract
Pteridine reductase 1 (PTR1) from Leishmania donovani is a short chain reductase that catalyses the NADPH-dependent reduction of folates and pterins. It has gained attention as a therapeutic target because it acts as a metabolic bypass for dihydrofolate reductase (DHFR) targeting drugs and is thought to be responsible for the failure of conventional therapies against the trypanosomatids. In the present study, we report the identification of thianthrene as a potent inhibitor of L. donovani PTR1 (LdPTR1) based on both structure-based virtual screening and experimental verification. Thianthrene displayed uncompetitive mixed type inhibition in a recombinant enzyme inhibition assay. In addition, cell based assays and flow cytometry showed that the intracellular amastigotes were inhibited by thianthrene in vitro. The results of our study could be considered for the development of novel therapeutics based on PTR1 inhibition.
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References
Barrack KL, Tulloch LB, Burke LA, Fyfe PK & Hunter WN 2010. Structure of recombinant Leishmania donovani pteridine reductase reveals a disordered active site. Acta Crystallogr Sect F Struct Biol Cryst Commun 67 33-37.
Bello AR, Nare B, Freedman D, Hardy L & Beverley SM 1994. PTR1: a reductase mediating salvage of oxidized pteridines and methotrexate resistance in the protozoan para-site Leishmania major. Proc Natl Acad Sci USA 91 11442-11446.
Bohm HJ 1992. LUDI: rule-based automatic design of new substituents for enzyme inhibitor leads. J Comput Aided Mol Des 6 593-606.
Carter KC, Henriquez FL, Campbell SA, Roberts CW, Nok A, Mullen AB & McFarlane E 2007. DNA vaccination against the parasite enzyme gamma-glutamylcysteine synthetase confers protection against Leishmania donovani in-fection. Vaccine 25 4502-4509.
Cavazzuti A, Paglietti G, Hunter WN, Gamarro F, Piras S, Loriga M, Allecca S, Corona P, McLuskey K, Tulloch L, Gibellini F, Ferrari S & Costi MP 2008 Discovery of potent pteridine reductase inhibitors to guide antiparasite drug development. Proc Natl Acad Sci U S A 105 1448-1453.
Gallivan JP & Dougherty DA 2000 A Computational Study of Cation−π Interactions vs Salt Bridges in Aqueous Media: Implications for Protein Engineering. J Am Chem Soc 122 870-874.
Gourley DG, Luba J, Hardy LW, Beverley SM & Hunter WN 1999 Crystallization of recombinant Leishmania major pteridine reductase 1 (PTR1). Acta Cryst D Biol Crystallogr 55 1608-1610.
Gourley DG, Schüttelkopf AW, Leonard GA, Luba J, Hardy LW,
Beverley SM & Hunter WN 2001 Pteridine reductase mechanism correlates pterin metabolism with drug resis-tance in trypanosomatid parasites. Nat Struct Biol 8 521-525.
Handman E 2001 Leishmaniasis: Current Status of Vaccine Development. Clin Microbiol Rev 14 229-243.
Hardy LW, Matthews W, Nare B & Beverly SM 1997. Biochemical and genetic tests for inhibitors of Leishmania pteridine pathways. Exp Parasitol 87 157-169.
Kaur J, Sundar S & Singh N 2010 Molecular docking, structure-activity relationship and biologic evaluation of the anti-cancer drug monastrol as pteridine reductase inhibitor in Leishmania donovani clinical isolate. J Antimicrob Chemother 65 1742-1748.
Kumar P, Kothari H & Singh N 2004 Overexpression in Escherichia Coli and purification of pteridine reductase 1 (PTR1) from a clinical isolate of Leishmania donovani. Protein Expr Purif 38 228-236.
Laskowski RA, Rullmannn JA, MacArthur MW, Kaptein R & Thornton JM 1996 AQUA and PROCHECK-NMR: programs for checking the quality of protein structures solved by NMR. J Biomol NMR 8 477-486.
Lüthy R, Bowie JU & Eisenberg D 1992 Assessment of protein models with three-dimensional profiles. Nature 356 83-85.
MartÃ-Renom MA, Stuart AC, Fiser A, Sánchez R, Melo F & Sali A 2000 Comparative protein structure modeling of genes and genomes. Annu Rev Biophys Biomol Struct 29 291-325.
McLuskey K, Gibellini F, Carvalho P, Avery MA & Hunter WN 2004 Inhibition of Leishmania major pteridine reductase by 2,4,6-triaminoquinazoline: structure of the NADPH ternary complex. Acta Crystallogr Sect D Biol Crystallogr 60 1780-1785.
Nare B, Hardy L & Beverley SM 1997b The roles of pteridine reductase 1 and dihydrofolate reductase-thymidylate synthase in pteridine metabolism in the protozoan parasite Leishmania major. J Biol Chem 272 13883-13891.
Nare B, Luba J, Hardy LW & Beverley SM 1997a New approaches to Leishmania chemotherapy: pteridine reductase 1 (PTR1) as a target and modulator of antifolate sensitivity. Parasitology 114 S101-110.
Perutz MF, Fermi G, Abraham DJ, Poyart C & Busaux E 1986 Hemoglobin as a receptor of drugs and peptides: x-ray studies of the stereochemistry of binding. J Am Chem Soc 108 1064-1078.
Shallom S, Zhang K, Jiang L & Rathod PK 1999 Essential protein-protein interactions between Plasmodium falciparum thymidylate synthase and dihydrofolate reductase domains. J Biol Chem 274 37781-37786.
Sienkiewicz N, Ong HB & Fairlamb AH 2010 Trypanosoma brucei pteridine reductase 1 is essential for survival in vitro and for virulence in mice. Mol Microbiol 77 658-671.
Singh N & Dube A 2004 Fluorescent Leishmania: application to antileishmanial drug testing. Am J Trop Med Hyg 71 400-402.
Singh N, Kumar P & Kaur J 2009 Pteridine reductase 1 as an antileishmanial drug target: Antifolate chemotherapy in leishmaniasis. VDM Verlag Dr. Müller.
Tulloch LB, Martini VP, Iulek J, Huggan JK, Lee JH, Gibson CL, Smith TK, Suckling CJ & Hunter WN 2010 Structure-Based Design of Pteridine Reductase Inhibitors Targeting African Sleeping Sickness and the Leishmaniases. J Med Chem 53 221-229.
Wang J, Leblanc E, Chang CF, Papadopoulou B, Bray T, Whiteley JM, Lin SX & Ouellette M 1997 Pterin and folate reduction by the Leishmania tarentolae H locus short-chain dehydrogenase/reductase PTR1. Arch Biochem Biophys 342 197-202.
Webster LT 1990 Goodman & Gilman’s The Pharmacological Basis of Therapeutics, edn 8, pp 954-1017. Eds LL Brunton, BA Chabner, BC Knollmann. New York: Perga-mon Press.
WHO 2012 Leishmaniasis Epidemics. In Programmes and projects. Retrieved from http://www.who.int/leishmaniasis/epidemic/en/
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