Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methionine aminopeptidase 2 (MetAP2) is responsible for the hydrolysis of the initiator methionine molecule from the majority of newly synthesized proteins. We have cloned the MetAP2 gene from the malaria parasite Plasmodium falciparum (PfMetAP2; GenBank accession number AF348320). The cloned PfMetAP2 has no intron, consists of 1,544 bp and encodes a protein of 354 amino acids with a molecular mass of 40,537 D and an overall base composition of 72.54% A + T. PfMetAP2 has 40% sequence identity with human MetAP2 and 45% identity with yeast MetAP2, and is located in chromosome 14 of P. falciparum. The three-dimensional structure of Pf MetAP2 has been modeled based on the crystal structure of human MetAP2, and several amino acid side chains protruding into the binding pocket that differ between the plasmodial and human enzyme have been identified. The specific MetAP2 inhibitors, fumagillin and TNP-470, potently blocked in vitro growth of P. falciparum and Leishmania donavani, with IC(50) values similar to the prototype drugs. Furthermore, in the case of P. falciparum, the chloroquine-resistant strains are equally susceptible to these two compounds.
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PMID:Angiogenesis inhibitors specific for methionine aminopeptidase 2 as drugs for malaria and leishmaniasis. 1181 23

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.
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PMID:Inhibitors of Plasmodium falciparum methionine aminopeptidase 1b possess antimalarial activity. 1698 82

The fumagillin family of natural products is known to inhibit angiogenesis through irreversible inhibition of human type 2 methionine aminopeptidase (MetAP2). Recently, fumagillin and TNP-470 were reported to possess antimalarial activity in vitro, and it was hypothesized that this inhibition was mediated by interaction with the putative malarial ortholog of human MetAP2. In this report, we have overexpressed and purified to near-homogeneity PfMetAP2 from bacteria, yeast, and insect cells. Although none of the recombinant forms of PfMetAP2 exhibited enzymatic activity in existing assays, PfMetAP2 proteins expressed in both yeast and insect cells were able to bind to fumagillin in a pull-down assay. The interaction between fumagillin and analogs with PfMetAP2 was further demonstrated using a newly established mammalian three-hybrid assay incorporating a conjugate between dexamethasone and fumagillin. Unlike human (Hs)MetAP2, it was found that PfMetAP2 is bound to fumagillin noncovalently. Importantly, a new analog of fumagillin, fumarranol, was demonstrated to interact with PfMetAP2 and inhibit the growth of both chloroquine-sensitive and drug-resistant Plasmodium falciparum strains in vitro. Antiparasite activity of fumagillin and fumarranol was also demonstrated in vivo using a mouse malaria model. These findings suggest that PfMetAP2 is a viable target, and fumarranol is a promising lead compound for the development of novel antimalarial agents.
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PMID:Fumagillin and fumarranol interact with P. falciparum methionine aminopeptidase 2 and inhibit malaria parasite growth in vitro and in vivo. 1924 10