D-mannonolactam amidrazone. A new mannosidase inhibitor that also inhibits the endoplasmic reticulum or cytoplasmic alpha-mannosidase.
The amidrazone of D-mannonolactam (see compound 5, Fig. 1) was synthesized chemically as a mimic of the mannopyranosyl cation and tested as a potential inhibitor of mannosidases. In this study compound 5 is shown to be a more general mannosidase inhibitor than other currently known compounds and exhibits properties not previously observed with any other mannosidase inhibitors. Thus D-mannonolactam amidrazone not only inhibits the Golgi mannosidase I (IC50 = 4 microM) and mannosidase II (IC50 = 90-100 nM), but it is the first inhibitor that has been shown to be a potent inhibitor of the soluble or endoplasmic reticulum alpha-mannosidase (IC50 = 1 microM). This compound also inhibited the aryl-mannosidases regardless of anomeric configuration although it was much more effective on enzymes recognizing alpha-linked mannose, i.e. jack bean and mung bean alpha-mannosidases (IC50 = 400 nM) as compared with fungal beta-mannosidase (IC50 = 150 microM). Mannonoamidrazone was tested in animal cell cultures using influenza virus-infected Madin-Darby canine kidney cells as a model system, and was found to prevent almost completely the formation of complex types of N-linked oligosaccharides with the formation of about equal amounts of Man9(GlcNAc)2 and Man8(GlcNAc)2 structures. Thus D-mannonolactam amidrazone is a potent but broad spectrum mannosidase inhibitor whose structure and properties should provide valuable insight into the design of other useful glycosidase inhibitors.
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Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock 72205.
Kaushal
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Papandreou
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Ganem
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Elbein
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D000818:Animals; D002478:Cells, Cultured; D002850:Chromatography, Gel; D003593:Cytoplasm / Q000201:enzymology*; D004285:Dogs; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D007887:Fabaceae / Q000201:enzymology; D008361:Mannosidases / Q000037:antagonists & inhibitors*; D008862:Microsomes, Liver / Q000201:enzymology; D010944:Plants / Q000201:enzymology; D010946:Plants, Medicinal; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D043323:alpha-Mannosidase
D011725:Pyridines; C074195:mannonolactam amidrazone; D008361:Mannosidases; D043323:alpha-Mannosidase