![]() donovani axenic amastigotes and this discrepancy could be due to poor cellular uptake due to the basicity of these compounds. There was little correlation between the enzyme potency of these inhibitors and their cellular activity against L. Several potent inhibitors were identified with marginal selectivity over the human enzyme. major NMT in a robust high-throughput biochemical assay. A focused set of 1,600 pyrazolyl sulfonamide compounds was screened against L. Here, we sought to pharmacologically validate this enzyme in Leishmania. N-Myristoyltransferase (NMT) remains one of the few genetically validated drug targets in these parasites. Available treatments are inadequate and there is a pressing need for new therapeutics. infantum, is responsible for ~30,000 deaths annually. The challenge in finding drug candidates remains to identify alternative strategies to address the drop-off in activity between enzyme inhibition and in vitro activity while maintaining sufficient selectivity over the human enzyme, both issues that continue to plague studies in this area.Ībstract = "Visceral leishmaniasis (VL), caused by the protozoan parasites Leishmania donovani and L. Thus, NMT is now a pharmacologically validated target in Leishmania. Oral dosing with compound 2 resulted in a 52% reduction in parasite burden in our mouse model of VL. Two un-biased approaches, namely screening against our cosmid-based overexpression library and thermal proteome profiling (TPP), confirm that DDD100097 (compound 2) acts on-target within parasites. donovani intracellular amastigotes (EC50 2.4 µM) and maintained a modest therapeutic window over the human enzyme. Although most of these compounds continued to suffer from relatively poor anti-leishmanial activity, our most potent inhibitor of LmNMT (DDD100097, Ki 0.34 nM), showed modest activity against L. Thus, a series of analogues were synthesised with less basic centres. ![]() Visceral leishmaniasis (VL), caused by the protozoan parasites Leishmania donovani and L.
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