Structural and functional-group tuning in the design of neuraminidase inhibitors.
Analogues of the disaccharide alpha-NeuAc-(2-->6)-beta-D-Gal-OR have been made by modifications at C-1 and C-6 of the galactose and at C-4 of the NeuAc unit, for structure-activity relationship studies with influenza virus neuraminidase. These studies indicate that for the influenza neuraminidase, a larger aglycon at C-1 of galactose is less preferred, whereas the restriction of the rotamer orientation at C-6 of galactose in the "tg" mode favors enzyme binding. Substitution at C-4 of the NeuAc unit has the most profound effect in the influenza neuraminidase hydrolysis and inhibition. For example, azido and acetamido groups at C-4 of the NeuAc units render the sialosides resistant to neuraminidase hydrolysis. However, these derivatives are not inhibitors of the neuraminidase, indicating their lack of binding. On the other hand, a 4-amino substitution of the NeuAc unit not only renders the corresponding sialosides neuraminidase-resistant, but also makes them potent neuraminidase inhibitors. This potent inhibition indicates that the 4-amino groups in these sialosides may engage in favorable interaction with amino acids at the neuraminidase active-site. The conclusion is also supported by docking studies of the carbohydrate structures at the neuraminidase active-site.
Sabesan
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Central Science and Engineering, Dupont Company, Wilmington, DE 19880-0328.
Neira
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Wasserman
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D000606:Amino Sugars / Q000737:chemistry / Q000494:pharmacology; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D004187:Disaccharides / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D005690:Galactose / Q000737:chemistry* / Q000378:metabolism*; D006027:Glycosides / Q000096:biosynthesis / Q000737:chemistry; D007700:Kinetics; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009975:Orthomyxoviridae / Q000201:enzymology; D011485:Protein Binding; D012794:Sialic Acids / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D000606:Amino Sugars; D004187:Disaccharides; D004791:Enzyme Inhibitors; D006027:Glycosides; D012794:Sialic Acids; D009439:Neuraminidase; D005690:Galactose