Fumagillin

Antibiotic and antiangiogenic agent; covalently binds and inhibits methionine aminopeptidase-2. Inhibits endothelial cell proliferation in vitro and tumor-induced angiogenesis in vivo. Also inhibits tumor growth in mice. Analog available, TNP 470 (Cat.No. 3750).

Fumagillin control of Nosema ceranae (Microsporidia:Nosematidae) infection in honey bee (Hymenoptera:Apidae) colonies in Argentina.[Pubmed:27393876]

Vet Ital. 2016 Jun 30;52(2):145-51.

Information on the longterm consequences of Nosema ceranae to honey bee lifespan and effectiveness of Nosema control with Fumagillin is scarce and not always consistent. Our objective in this study was to evaluate the effectiveness of the antibiotic Fumagillin to control N. ceranae in hives in EastCentral Argentina. Honey bee hives were assigned to 3 experimental treatments, a control group with untreated hives, a preventive strategy group with hives treated monthly, and a monitoring strategy group with hives treated according to a N. ceranae threshold level. Apiaries were monitored monthly during FallWinter 2009 and 2010 and N. ceranae spore intensity and honey bee colony strength measures were estimated. Fumagillintreated colonies had reduced N. ceranae spores load in 2010 compared to control colonies. However, there was no significant difference between treated and control groups for colony strength measures including adult bee population, bee brood availability, honey, or pollen. Fumagillin treatment reduced N. ceranae intensities but had little effect on colonies. The bee population during Winter was reduced in treated as well as in control colonies. Our results clarify that Fumagillin treatment should be at least reviewed and that further research should be conducted to acquire a more complete perspective of Nosemosis disease.

Successful Treatment of Disseminated Anncaliia algerae Microsporidial Infection With Combination Fumagillin and Albendazole.[Pubmed:27704013]

Open Forum Infect Dis. 2016 Jul 29;3(3):ofw158.

Anncaliia algerae myositis is a life-threatening, emerging microsporidiosis among immunocompromised hosts. We report a case of disseminated A algerae infection in a man previously treated with alemtuzumab. Due to failure of albendazole-based therapy, Fumagillin was added as a novel approach to management, with a good clinical response and patient survival.

Nosema ceranae Winter Control: Study of the Effectiveness of Different Fumagillin Treatments and Consequences on the Strength of Honey Bee (Hymenoptera: Apidae) Colonies.[Pubmed:28025388]

J Econ Entomol. 2017 Feb 1;110(1):1-5.

Overview: In Uruguay, colonies of honey bees moving to Eucalyptus grandis plantation in autumn habitually become infected with the microsporidian Nosema ceranae , a parasite that attacks the digestive system of bees. Beekeepers attributed to N. ceranae depopulation of the colonies that often occurs at the end of the blooming period, and many use the antibiotic Fumagillin to reduce the level of infection. The aim of this study was to compare the effectiveness of four different Fumagillin treatments and determine how this antibiotic affects the strength of the colonies during the winter season. The colonies treated with Fumagillin in July showed less spore load at the end of applications, being the most effective the following treatments: the four applications sprayed over bees of 30 mg of Fumagillin in 100 ml of sugar syrup 1:1, and four applications of 90 mg of Fumagillin in 250 ml of sugar syrup 1:1 using a feeder. However, 2 month after the treatment applications, the colonies treated with Fumagillin were the same size as the untreated colonies. In September, the colonies treated and not treated with Fumagillin did not differ in colony strength (adult bee population and brood area) or spores abundance. Our study demonstrates that Fumagillin treatment temporarily decreased the spore load of N. ceranae , but this was not reflected in either the size of the colonies or the probability of surviving the winter regardless of the dose or the administration strategy applied. Given the results obtained, we suggest to not perform the pharmacological treatment under the conditions described in the experiment. Resumen: En Uruguay las colonias de abejas meliferas que se trasladan a las forestaciones de Eucalyptus grandis en otono indefectiblemente se infectan con el microsporido Nosema ceranae , parasito que ataca el sistema digestivo de las abejas. Los apicultores atribuyen a N. ceranae el despoblamiento de las colonias que ocurre con frecuencia al terminar el periodo de floracion y muchos emplean el antibiotico fumagilina para reducir el nivel de infeccion. El objetivo de este estudio fue comparar la eficacia de cuatro tratamientos diferentes con fumagilina y determinar como incide en la fortaleza de las colonias durante la invernada. Las colonias tratadas con fumagilina en julio presentaron una menor carga de esporas al terminar las aplicaciones, siendo los tratamientos mas eficaces el de 4 aplicaciones mediante asperjado sobre las abejas de 30 mg de fumagilina en 100 ml de jarabe de azucar 1:1, y el de 4 aplicaciones de 90 mg de fumagilina en 250 ml de jarabe de azucar 1:1 utilizando un alimentador. Sin embargo, durante el periodo de experimentacion, las colonias tratadas con antibiotico presentaron igual tamano que las colonias no tratadas. En setiembre, las colonias tratadas y no tratadas con fumagilina no se diferenciaron en la intensidad de infeccion ni en su tamano. En las condiciones en que se realizo el estudio, la aplicacion de fumagilina disminuyo temporalmente la carga de esporas de N. ceranae pero esto no se reflejo en el tamano de las colonias ni en la probabilidad de sobrevivir el invierno.

Spiroepoxytriazoles Are Fumagillin-like Irreversible Inhibitors of MetAP2 with Potent Cellular Activity.[Pubmed:26686773]

ACS Chem Biol. 2016 Apr 15;11(4):1001-11.

Methionine aminopeptidases (MetAPs) are responsible for the cotranslational cleavage of initiator methionines from nascent proteins. The MetAP2 subtype is up-regulated in many cancers, and selective inhibition of MetAP2 suppresses both vascularization and growth of tumors in animal models. The natural product Fumagillin is a selective and potent irreversible inhibitor of MetAP2, and semisynthetic derivatives of Fumagillin have shown promise in clinical studies for the treatment of cancer, and, more recently, for obesity. Further development of Fumagillin derivatives has been complicated, however, by their generally poor pharmacokinetics. In an attempt to overcome these limitations, we developed an easily diversifiable synthesis of a novel class of MetAP2 inhibitors that were designed to mimic Fumagillin's molecular scaffold but have improved pharmacological profiles. These substances were found to be potent and selective inhibitors of MetAP2, as demonstrated in biochemical enzymatic assays against three MetAP isoforms. Inhibitors with the same relative and absolute stereoconfiguration as Fumagillin displayed significantly higher activity than their diastereomeric and enantiomeric isomers. X-ray crystallographic analysis revealed that the inhibitors covalently modify His231 in the MetAP2 active site via ring-opening of a spiroepoxide. Biochemically active substances inhibited the growth of endothelial cells and a MetAP2-sensitive cancer cell line, while closely related inactive isomers had little effect on the proliferation of either cell type. These effects correlated with altered N-terminal processing of the protein 14-3-3-gamma. Finally, selected substances were found to have improved stabilities in mouse plasma and microsomes relative to the clinically investigated Fumagillin derivative beloranib.

A re-evaluation of fumagillin selectivity towards endothelial cells.[Pubmed:11848509]

Anticancer Res. 2001 Sep-Oct;21(5):3457-60.

We have re-evaluated the selectivity of Fumagillin against endothelial cell proliferation and compared it to the reported selectivity of its potent analog TNP-470. We showed that Fumagillin does not inhibit endothelial cell proliferation in a specific manner, but on the contrary it inhibits the proliferation of other cell types at the same range of concentrations. Furthermore, the IC50 values of Fumagillin for endothelial cells are two orders of magnitude higher than those values reported for TNP-470 on endothelial cells; on the contrary, the IC50 value of Fumagillin for human breast cancer MDA-MB231 cells is four orders of magnitude lower than the value reported for TNP-470 on the same cell line.

The anti-angiogenic agent fumagillin covalently modifies a conserved active-site histidine in the Escherichia coli methionine aminopeptidase.[Pubmed:9770455]

Proc Natl Acad Sci U S A. 1998 Oct 13;95(21):12153-7.

Methionine aminopeptidase (MetAP) exists in two forms (type I and type II), both of which remove the N-terminal methionine from proteins. It previously has been shown that the type II enzyme is the molecular target of Fumagillin and ovalicin, two epoxide-containing natural products that inhibit angiogenesis and suppress tumor growth. By using mass spectrometry, N-terminal sequence analysis, and electronic absorption spectroscopy we show that Fumagillin and ovalicin covalently modify a conserved histidine residue in the active site of the MetAP from Escherichia coli, a type I enzyme. Because all of the key active site residues are conserved, it is likely that a similar modification occurs in the type II enzymes. This modification, by occluding the active site, may prevent the action of MetAP on proteins or peptides involved in angiogenesis. In addition, the results suggest that these compounds may be effective pharmacological agents against pathogenic and resistant forms of E. coli and other microorganisms.

Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth.[Pubmed:1701033]

Nature. 1990 Dec 6;348(6301):555-7.

Neovascularization is critical for the growth of tumours and is a dominant feature in a variety of angiogenic diseases such as diabetic retinopathy, haemangiomas, arthritis and psoriasis. Recognition of the potential therapeutic benefit of controlling unabated capillary growth has led to a search for safe and effective angiogenesis inhibitors. We report here the synthesis of a family of novel inhibitors that are analogues of Fumagillin, a naturally secreted antibiotic of Aspergillus fumigatus fresenius. We first isolated this fungus from a contaminated culture of capillary endothelial cells. Purified Fumagillin inhibited endothelial cell proliferation in vitro and tumour-induced angiogenesis in vivo; it also inhibited tumour growth in mice, but prolonged administration was limited because it caused severe weight loss. Synthesis of Fumagillin analogues yielded potent angiogenesis inhibitors ('angioinhibins') which suppress the growth of a wide variety of tumours with relatively few side-effects.

Fumagillin(NSC9168) is a complex biomolecule and used as an antimicrobial agent. Fumagillin can inhibits HIV‐1 infection through the inhibition of HIV-1 viral protein R (Vpr) activity.

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