Inhibitors for Plasmodium falciprum methionine aminopeptidase 1b possess antimalarial activity both in vitro and in vivo

The possibility of using Plasmodium falciprum methionine aminopeptidase type 1b (PfMetAP1b) as a valid target for antimalarials development was explored. A MetAP enzyme assay was used in a high-throughput screening of a 70,000 compound library. 2-(2-pyridinyl)-Pyrimidine was identified as a novel class of PfMetAP1b inhibitor. XC11, the most potent hit, had an IC50 of 112 nM and was more than 100 folds selective for PfMetAP1b over the other 3 PfMetAPs. Upon treatment of P. falciprum strain ITG (chloroquine, CQ resistant) in vitro with XC11, the parasites arrested at early ring stage which correlated to the intraerythrocytic protein expression profile indicating the existence of PfMetAP1b mainly found at trophozoite stage. XC11 inhibited the proliferation of P. falciprum strains 3D7 (CQ sensitive) and Dd2 (multi-drug resistant) in vitro (IC50= 3.37μM and 3.31μM respectively) while it was less toxic to primary human fibroblasts (IC50 >100μM). Most importantly, in mice models for both CQ sensitive and resistant malarial strains, XC11 dose dependently inhibited the blood level of parasitemia and showed curative effect (up to 80%) with a treatment regime of up to 20mg/kg, twice a day for 4 days right after infection. These results suggest that XC11 may serve as a lead, and PfMetAP1b is a promising target, for the development of novel antimalarial drugs. Meanwhile, this novel class of PfMetAP1b inhibitor could be a good tool to better understand the physiological function of this enzyme.