title: Structure-based design of pteridine reductase inhibitors targeting African sleeping sickness and the leishmaniases.
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 a molecular 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.
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD15EH, UK.
authors.forename: Lindsay B
authors.initials: LB
authors.lastname: Tulloch
authors.forename: Viviane P
authors.initials: VP
authors.lastname: Martini
authors.forename: Jorge
authors.initials: J
authors.lastname: Iulek
authors.forename: Judith K
authors.initials: JK
authors.lastname: Huggan
authors.forename: Jeong Hwan
authors.initials: JH
authors.lastname: Lee
authors.forename: Colin L
authors.initials: CL
authors.lastname: Gibson
authors.forename: Terry K
authors.initials: TK
authors.lastname: Smith
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Suckling
authors.forename: William N
authors.initials: WN
authors.lastname: Hunter
mesh_terms: D020134:Catalytic Domain; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018320:Leishmania major / Q000187:drug effects / Q000201:enzymology; D007896:Leishmaniasis / Q000188:drug therapy* / Q000469:parasitology*; D008958:Models, Molecular; D015394:Molecular Structure; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology; D014353:Trypanosomiasis, African / Q000188:drug therapy* / Q000469:parasitology*
chemical_list: D004791:Enzyme Inhibitors; D010088:Oxidoreductases; C085592:pteridine reductase; D013762:Tetrahydrofolate Dehydrogenase