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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

From the Cover: Inhibitors of Plasmodium falciparum methionine aminopeptidase 1b possess antimalarial activity.

With >1 million deaths annually, mostly among children in sub-Saharan Africa, malaria poses one of the most critical challenges in medicine today. Although introduction of the artemisinin class of antimalarial drugs has offered a temporary solution to the problem of drug resistance, new antimalarial drugs are needed to ensure effective control of the disease in the future. Herein, we have investigated members of the methionine aminopeptidase family as potential antimalarial targets. The Plasmodium falciparum methionine aminopeptidase 1b (PfMetAP1b), one of four MetAP proteins encoded in the P. falciparum genome, was cloned, overexpressed, purified, and used to screen a 175,000-compound library for inhibitors. A family of structurally related inhibitors containing a 2-(2-pyridinyl)-pyrimidine core was identified. Structure/activity studies led to the identification of a potent PfMetAP1b inhibitor, XC11, with an IC(50) of 112 nM. XC11 was highly selective for PfMetAP1b and did not exhibit significant cytotoxicity against primary human fibroblasts. Most importantly, XC11 inhibited the proliferation of P. falciparum strains 3D7 [chloroquine (CQ)-sensitive] and Dd2 (multidrug-resistant) in vitro and is active in mouse malaria models for both CQ-sensitive and CQ-resistant strains. These results suggest that PfMetAP1b is a promising target and XC11 is an important lead compound for the development of novel antimalarial drugs.[1]


  1. From the Cover: Inhibitors of Plasmodium falciparum methionine aminopeptidase 1b possess antimalarial activity. Chen, X., Chong, C.R., Shi, L., Yoshimoto, T., Sullivan, D.J., Liu, J.O. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
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