Angiogenesis Inhibitors Specific for Methionine Aminopeptidase 2 as Drugs for Malaria and Leishmaniasis

Zhang, Peng; Nicholson, Diarmuid E.; Bujnicki, Janusz M.; Su, Xin-zhuan; Brendle, James J.; Ferdig, Michael T.; Kyle, Dennis E.; Milhous, Wilbur K.; Chiang, Peter K.

doi:10.1159/000048197

Cited by 14 publications

(15 citation statements)

References 19 publications

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“…Fumagillin covalently binds to a histidine moiety (His 231 ) within the enzymatic active site of the methionine aminopeptidase type 2 (MetAP-2) enzyme (Griffith et al 1997;Sin et al 1997;Liu et al 1998;Zhang et al 2002). resulting in the irreversible opening of the spiroepoxide group on the core cyclohexane skeleton of fumagillin.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Fumagilin-B® and other potential alternative chemotherapies against Nosema ceranae-infected honeybees (Apis mellifera) in cage trial assays

Heever¹,

Thompson²,

Otto

et al. 2015

Apidologie

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Section: Introductionmentioning

confidence: 99%

Evaluation of Fumagilin-B® and other potential alternative chemotherapies against Nosema ceranae-infected honeybees (Apis mellifera) in cage trial assays

Heever¹,

Thompson²,

Otto

et al. 2015

Apidologie

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“…The recent discovery that cytoplasmic MAP2s are the specific cellular target of natural compounds like fumagillin, acting as antiangiogenic, antitumoral, or immunosuppressive agents, has revived interest in NME (Ingber et al, 1990;Griffith et al, 1997Griffith et al, , 1998Sin et al, 1997;Turk et al, 1999;Towbin et al, 2003). Several of these compounds have also been shown to have antiproliferative effects in unicellular eukaryotes, such as ameba (Killough et al, 1952), microsporidians (Weiss et al, 2001), trypanosomatida, and apicomplexa (Zhang et al, 2002), all of which cause severe parasitic diseases in humans. Significant progress has recently been made in the characterization of this process in higher eukaryotes (for review, see Giglione et al, 2004).…”

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confidence: 99%

Functional and Developmental Impact of Cytosolic Protein N-Terminal Methionine Excision in Arabidopsis

et al. 2005

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Protein N-terminal methionine (Met) excision (NME) is carried out by two types of Met aminopeptidases (MAPs), MAP1 and MAP2, in eukaryotes. Three enzymes, MAP1A, MAP2A, and MAP2B, have been identified in the cytoplasm of Arabidopsis (Arabidopsis thaliana). MAP transcript quantification revealed a predominance of MAP2B and developmental and organ-specific regulation of both MAP1A and MAP2s. By combining reverse genetics and reverse chemogenomics in transgenic plant lines, we have devised specific and reversible switches for the investigation of the role of cytoplasmic NME in Arabidopsis and of the respective contributions of the two types of cytoplasmic MAPs throughout development. dsRNA interference and knockout (KO) plant lines targeting either MAP1A alone or both MAP2s simultaneously were constructed and shown to display wild-type phenotypes. In the MAP1A KO context, modulating MAP2 activity by treatment with various concentrations of the specific drug fumagillin impaired plant development, with particularly strong effects on the root system. Reciprocally, complete MAP2 inhibition in various MAP1A knocked-down genetic backgrounds also generated a gradient of developmentally abnormal plants, but the effects on the root system were milder than in the KO context. In the absence of MAP2 activity, the severity of the phenotype in the MAP1A knocked-down lines was correlated to the extent of MAP1A mRNA accumulation. Complete cytoplasmic NME inactivation blocked development after plant germination. Thus, in plants, (1) cytoplasmic NME is essential; (2) MAP1A and MAP2s are functionally interchangeable, which is not the case in fungi and animals, as a complete block of either MAP-type activity does not cause any visible molecular or phenotypic effect; and (3) a minimal level of cytoplasmic MAP is required for normal development.

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“…Differences between the human and microsporidian MetAP2s in the surface residues and the absence of the N-terminal polylysine region in the microsporidian MetAP2 suggested that more selective compounds could be designed (48,49,53). Fumagillin and TNP-470 also inhibited replication of Plasmodium falciparum and Leishmania donovani in vitro, and it has been suggested that differences between the MetAP2s of these parasites and human MetAP2 could be exploited for more selective derivatives of fumagillin (54).…”

Section: Discussionmentioning

confidence: 99%

Antimicrosporidial Activities of Fumagillin, TNP-470, Ovalicin, and Ovalicin Derivatives In Vitro and In Vivo

Didier

Phillips²,

Kuebler³

et al. 2006

Antimicrob Agents Chemother

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Therapies for microsporidiosis in humans are limited, and fumagillin, which appears to be the most broadly effective antimicrosporidial drug, is considered to be moderately toxic. The purpose of this study was to apply an in vitro drug screening assay for Encephalitozoon intestinalis and Vittaforma corneae and an in vivo athymic mouse model of V. corneae infection to assess the efficacy of TNP-470 (a semisynthetic analogue of fumagillin), ovalicin, and eight ovalicin derivatives. TNP-470, ovalicin, and three of the ovalicin derivatives inhibited both E. intestinalis and V. corneae replication by more than 70% in vitro. Another three of the ovalicin derivatives inhibited one of the two microsporidian species by more than 70%. None of the treated athymic mice survived the V. corneae infection, but they did survive statistically significantly longer than the untreated controls after daily treatment with fumagillin administered at 5, 10, and 20 mg/kg of body weight subcutaneously (s.c.), TNP-470 administered at 20 mg/kg intraperitoneally (i.p.), or ovalicin administered at 5 mg/kg s.c. Of two ovalicin derivatives that were assessed in vivo, NSC 9665 given at 10 mg/kg i.p. daily also statistically significantly prolonged survival of the mice. No lesions associated with drug toxicity were observed in the kidneys or livers of uninfected mice treated with these drugs at the highest dose of 20 mg/kg daily. These results thus support continued studies to identify more effective fumagillin-related drugs for treating microsporidiosis.

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Angiogenesis Inhibitors Specific for Methionine Aminopeptidase 2 as Drugs for Malaria and Leishmaniasis

Cited by 14 publications

References 19 publications

Evaluation of Fumagilin-B® and other potential alternative chemotherapies against Nosema ceranae-infected honeybees (Apis mellifera) in cage trial assays

Evaluation of Fumagilin-B® and other potential alternative chemotherapies against Nosema ceranae-infected honeybees (Apis mellifera) in cage trial assays

Functional and Developmental Impact of Cytosolic Protein N-Terminal Methionine Excision in Arabidopsis

Antimicrosporidial Activities of Fumagillin, TNP-470, Ovalicin, and Ovalicin Derivatives In Vitro and In Vivo

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