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Comparative mapping of on-targets and off-targets for the discovery of anti-trypanosomatid folate pathway inhibitors

Biochim Biophys Acta Gen Subj. 2017-12; 
Panecka-HofmanJoanna, PöhnerIna, SpyrakisFrancesca, ZeppelinTalia, Di PisaFlavio, Dello IaconoLucia, BonucciAlessio, QuotadamoAntonio, VenturelliAlberto, ManganiStefano, CostiMaria Paola, WadeRebec
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Gene Synthesis … The synthetic gene encoding for TcDHFR–TS (purchased from GenScript USA Inc., www.genscript.com), was expressed in E. coli, then protein was harvested and purified, following the experimental procedure described in detail in the Supplementary material (Section S1) … Get A Quote

摘要

Multi-target approaches are necessary to properly analyze or modify the function of a biochemical pathway or a protein family. An example of such a problem is the repurposing of the known human anti-cancer drugs, antifolates, as selective anti-parasitic agents. This requires considering a set of experimentally validated protein targets in the folate pathway of major pathogenic trypanosomatid parasites and humans: (i) the primary parasite on-targets: pteridine reductase 1 (PTR1) (absent in humans) and bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS), (ii) the primary off-targets: human DHFR and TS, and (iii) the secondary on-target: human folate receptor β, a folate/antifolate trans... More

关键词

Anti-parasitic drug,Enzyme inhibitor,Folate pathway,Selective inhibition,Structure-based drug design,Trypanosoma