Structure-based design of pteridine reductase inhibitors targeting African sleeping sickness and the leishmaniases

Lindsay B. Tulloch, Viviane P. Martini, Jorge Iulek, J. Huggan, Jeong Hwan Lee, C.L. Gibson, Terry K. Smith, C.J. Suckling, William N. Hunter

Research output: Contribution to journalArticle

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Abstract

Pteridine reductase (PTR1) is a target for drug development against Trypanosoma and Leishmania species, parasites that cause serious tropical diseases and for which therapies are inadequate. We adopted a structure-based approach to the design of novel PTR1 inhibitors based on three molecular scaffolds. A series of compounds, most newly synthesized, were identified as inhibitors with PTR1-species specific properties explained by structural differences between the T. brucei and L. major enzymes. The most potent inhibitors target T. brucei PTR1, and two compounds displayed antiparasite activity against the bloodstream form of the parasite. PTR1 contributes to antifolate drug resistance by providing amolecular bypass of dihydrofolate reductase(DHFR) inhibition.Therefore, combining PTR1 and DHFR inhibitors might improve therapeutic efficacy. We tested two new compounds with known DHFR inhibitors. A synergistic effect was observed for one particular combination highlighting the potential of such an approach for treatment of African sleeping sickness.
LanguageEnglish
Pages221-229
Number of pages9
JournalJournal of Medicinal Chemistry
Volume53
Issue number1
Early online date16 Nov 2009
DOIs
Publication statusPublished - 2010

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African Trypanosomiasis
Folic Acid Antagonists
Parasites
Trypanosoma
Tetrahydrofolate Dehydrogenase
Leishmania
Drug Resistance
Enzymes
Therapeutics
Pharmaceutical Preparations
pteridine reductase

Keywords

  • medicinal chemistry
  • pteridine reductase inhibitors
  • sleeping sickness
  • leishmaniases

Cite this

Tulloch, L. B., Martini, V. P., Iulek, J., Huggan, J., Lee, J. H., Gibson, C. L., ... Hunter, W. N. (2010). Structure-based design of pteridine reductase inhibitors targeting African sleeping sickness and the leishmaniases. Journal of Medicinal Chemistry, 53(1), 221-229. https://doi.org/10.1021/jm901059x
Tulloch, Lindsay B. ; Martini, Viviane P. ; Iulek, Jorge ; Huggan, J. ; Lee, Jeong Hwan ; Gibson, C.L. ; Smith, Terry K. ; Suckling, C.J. ; Hunter, William N. / Structure-based design of pteridine reductase inhibitors targeting African sleeping sickness and the leishmaniases. In: Journal of Medicinal Chemistry. 2010 ; Vol. 53, No. 1. pp. 221-229.
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Tulloch, LB, Martini, VP, Iulek, J, Huggan, J, 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' Journal of Medicinal Chemistry, vol. 53, no. 1, pp. 221-229. https://doi.org/10.1021/jm901059x

Structure-based design of pteridine reductase inhibitors targeting African sleeping sickness and the leishmaniases. / Tulloch, Lindsay B.; Martini, Viviane P.; Iulek, Jorge; Huggan, J.; Lee, Jeong Hwan; Gibson, C.L.; Smith, Terry K.; Suckling, C.J.; Hunter, William N.

In: Journal of Medicinal Chemistry, Vol. 53, No. 1, 2010, p. 221-229.

Research output: Contribution to journalArticle

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AU - Martini, Viviane P.

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AU - Gibson, C.L.

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AB - Pteridine reductase (PTR1) is a target for drug development against Trypanosoma and Leishmania species, parasites that cause serious tropical diseases and for which therapies are inadequate. We adopted a structure-based approach to the design of novel PTR1 inhibitors based on three molecular scaffolds. A series of compounds, most newly synthesized, were identified as inhibitors with PTR1-species specific properties explained by structural differences between the T. brucei and L. major enzymes. The most potent inhibitors target T. brucei PTR1, and two compounds displayed antiparasite activity against the bloodstream form of the parasite. PTR1 contributes to antifolate drug resistance by providing amolecular bypass of dihydrofolate reductase(DHFR) inhibition.Therefore, combining PTR1 and DHFR inhibitors might improve therapeutic efficacy. We tested two new compounds with known DHFR inhibitors. A synergistic effect was observed for one particular combination highlighting the potential of such an approach for treatment of African sleeping sickness.

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