Antiparasitic activities of novel, orally available fumagillin analogs (original) (raw)

2009, Bioorganic & Medicinal Chemistry Letters

Fumagillin, an irreversible inhibitor of MetAP2, has been shown to potently inhibit growth of malaria parasites in vitro. Here, we demonstrate activity of fumagillin analogs with an improved pharmacokinetic profile against malaria parasites, trypanosomes, and amoebas. A subset of the compounds showed efficacy in a murine malaria model. The observed SAR forms a basis for further optimization of fumagillin based inhibitors against parasitic targets by inhibition of MetAP2. The sesquiterpene fumagillin 1, produced by Aspergillus fumigatus, has been extensively studied for its antimicrobial activity. 1 While toxic, it is employed in veterinary applications and to a limited degree in humans, particularly in immunocompromised individuals. A renewed interest in fumagillin, driven by recognition of its anticancer properties, led to identification of its molecular target, methionine aminopeptidase-2 (MetAP2). 2 MetAP2 is a cytosolic enzyme which removes methionine from the amino terminus of newly synthesized proteins for subsequent post-translational modifications (e.g. myristoylation), which are required for stability, activity, and intracellular localization. 3, 4 A related isoform, MetAP1, can process many of the same substrates, but its relative activity differs from that of MetAP2 based on the nature of the amino acid residues flanking the cleavage site, primarily the residue immediately adjacent to the N-terminal methionine. Fumagillin and structural analogues, such as TNP-470 (AGM-1470), 2a, selectively inhibit MetAP2 enzymatic activity through irreversible, covalent bond formation with histidine-231 in the active site of the enzyme. 5, 6