Influence of Side Chain Conformation on the Activity of Glycosidase Inhibitors

Substrate side chain conformation impacts reactivity during glycosylation and glycoside hydrolysis and is restricted by many glycosidases and glycosyltransferases during catalysis. We show that the side chains of gluco and manno iminosugars can be restricted to predominant conformations by strategic installation of a methyl group. Glycosidase inhibition studies reveal that iminosugars with the gauche,gauche side chain conformations are 6- to 10-fold more potent than isosteric compounds with the gauche,trans conformation; a manno-configured iminosugar with the gauche,gauche conformation is a 27-fold better inhibitor than 1-deoxymannojirimycin. The results are discussed in terms of the energetic benefits of preorganization, particularly when in synergy with favorable hydrophobic interactions. The demonstration that inhibitor side chain preorganization can favorably impact glycosidase inhibition paves the way for improved inhibitor design through conformational preorganization.

Automated summary

The conformation of substrate side chain affects reactivity in glycosylation and glycoside hydrolysis reactions and is restricted during catalysis by many enzymes. This study demonstrates that gluco and manno iminosugars can be restricted to specific conformations through strategic installation of a methyl group. Inhibition studies show that iminosugars with gauche,gauche conformation are 6-10 times more potent than those with gauche,trans conformation, and a manno-configured iminosugar with gauche,gauche conformation is 27 times better inhibitor than 1-deoxymannojirimycin. These results highlight the importance of side chain preorganization for improved inhibitor design in glycosidase inhibition.