Fumagillin and fumarranol interact with P. falciparum methionine aminopeptidase 2 and inhibit malaria parasite growth in vitro and in vivo.
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.
Chen
Xiaochun
X
Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
Xie
Suji
S
Bhat
Shridhar
S
Kumar
Nirbhay
N
Shapiro
Theresa A
TA
Liu
Jun O
JO
D000595:Amino Acid Sequence; D000626:Aminopeptidases / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D000818:Animals; D000962:Antimalarials / Q000378:metabolism / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D003510:Cyclohexanes / Q000378:metabolism / Q000494:pharmacology*; D004926:Escherichia coli / Q000235:genetics; D005231:Fatty Acids, Unsaturated / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008288:Malaria / Q000188:drug therapy; D008666:Metalloendopeptidases / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development; D011485:Protein Binding; D015800:Protozoan Proteins / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics; D016415:Sequence Alignment; D012717:Sesquiterpenes / Q000378:metabolism / Q000494:pharmacology*
D000962:Antimalarials; D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D012717:Sesquiterpenes; C514166:fumarranol; C026211:fumagillin; D000626:Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases