Abstract
Giardiasis, caused by the intestinal parasite Giardia lamblia, is a severe diarrheal disease, endemic in poverty-stricken regions of the world, and also a common infection in developed countries. The available therapeutic options are associated with adverse effects, and G. lamblia resistance to the standard-of-care drugs is spreading. Fumagillin, an antimicrosporidiosis drug, is a therapeutic agent with potential for the treatment of giardiasis. However, it exhibits considerable, albeit reversible, toxicity when used to treat immunocompromised microsporidiosis patients. Fumagillin is also a highly unstable compound. To address these liabilities, we designed and synthesized stable fumagillol derivatives with lower levels of permeation across polarized epithelial Caco-2 cells and better potency against G. lamblia trophozoites than fumagillin. Metronidazole-resistant G. lamblia strains were also susceptible to the new fumagillol derivatives. In addition, these compounds were more potent against the amebiasis-causing parasite Entamoeba histolytica than fumagillin. Two compounds exhibited better thermal and acid stability than fumagillin, which should prolong the drug shelf life and reduce compound degradation in the stomach. Studies with a mouse model of giardiasis with the most stable compound, 4-(((((3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl)oxy)carbonyl)amino)benzoic acid (compound 9), revealed that it had better efficacy (effective dose [ED]) than fumagillin at both the fully curative dose (the 100% ED) of 6.6 mg/kg of body weight and a 50% ED of 0.064 mg/kg. Plasma pharmacokinetics revealed the slow absorption of compound 9 through the gut, consistent with the in vitro characterization in Caco-2 cells. An acute-dose study yielded a maximum tolerated dose (MTD) of 1,500 mg/kg, 227-fold higher than the fully curative dose. Thus, along with improved stability, compound 9 also exhibited an excellent therapeutic window.
Highlights
Giardiasis, caused by the intestinal parasite Giardia lamblia, is a severe diarrheal disease, endemic in poverty-stricken regions of the world, and a common infection in developed countries
The current studies focus on the C-6 position of fumagillol because several crystal structures of methionine aminopeptidase 2 (MetAP2) bound with inhibitors show that the C-6 substituents are oriented toward the solvent
These inhibit G. lamblia MetAP2, the sole MetAP produced by the organism
Summary
Giardiasis, caused by the intestinal parasite Giardia lamblia, is a severe diarrheal disease, endemic in poverty-stricken regions of the world, and a common infection in developed countries. Metronidazole-resistant G. lamblia strains were susceptible to the new fumagillol derivatives These compounds were more potent against the amebiasis-causing parasite Entamoeba histolytica than fumagillin. A detailed giardiasis study in France reported metronidazole resistance as well as resistance to albendazole, a benzimidazole derivative standard-of-care drug used in Europe [12]. These studies showed Ͼ20% multidrug resistance in both the patients and mice infected with the human drugresistant G. lamblia strain. Proliferation assays measuring the minimum lethal concentration (MLC) in G. lamblia strains confirmed the potency of fumagillin and determined MLCs of 0.7 M and 0.26 M for the WB and GS strains, respectively [18]
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