Recent advances in glycoside hydrolase family 20 and 84 inhibitors: Structures, inhibitory mechanisms and biological activities

Glycoside hydrolase family 20 (GH20) beta-N-acetyl-D-hexosaminidase (Hex) catalyzes the cleavage of glycosidic linkages in glycans, glycolipids and glycoproteins, and is involved in glycoprotein modification, metabolism of glycoconjugate and the degradation of chitin in fungal cell walls and arthropod exoskeletons. GH84 O-beta-N-acetylD-glucosaminidase (OGA), which is mechanistically similar related to GH20, participates in the O-GlcNAcylation modification, hydrolyzing the O-GlcNAc moiety from protein acceptors. Hex and OGA are of interest due to their potential for the treatment of disorder diseases and plant protection. Hex inhibitors act as molecular chaperones to treat lysosomal storage disease and as growth regulators to arrest insect molting. Inhibition of OGA is a promising therapeutic approach to treat tau pathology in neurodegenerative diseases such as Alzheimer's disease. However, since Hex and OGA exhibit similar active sites, there are challenges in designing highly selective inhibitors. The elucidation of the structural basis of the catalytic mechanism and substrate binding mode of Hex and OGA has provided core information for virtual screening and rational design of inhibitors. A large number of high-potency and selective inhibitors have been developed in the last five years. In this review, we focus on the recent advances in the structural modification, inhibitory activity, binding mechanisms and biological evaluation of Hex and OGA inhibitors, which will facilitate the development of new drugs and agrochemicals.

Automated summary

Glycoside hydrolase family 20 (GH20) and GH84 are involved in glycoprotein modification, metabolism, and degradation, with potential applications in disease treatment and plant protection. The challenges lie in designing highly selective inhibitors due to the similarity of their active sites. Understanding the catalytic mechanism and substrate binding mode of Hex and OGA provides crucial information for inhibitor design.