Human N-acetyl-beta-hexosaminidase (Hex) isozymes are considered to be important targets for drug discovery. They are directly linked to osteoarthritis because Hex is the predominant glycosidase released by chondrocytes to degrade glycosaminoglycan. Hex is also associated with lysosomal storage disorders. We report the discovery of GlcNAc-type iminocyclitiols as potent and selective Hex inhibitors, likely contributed by the gain of extra electrostatic and hydrophobic interactions. The most potent inhibitor had a K(i) of 0.69 nM against human Hex B and was 2.5 x 10(5) times more selective for Hex B than for a similar human enzyme O-GlcNAcase. These glycosidase inhibitors were shown to modulate intracellular levels of glycolipids, including ganglioside-GM2 and asialoganglioside-GM2.

Zwei Schleifen, die sich nach innen zum aktiven Zentrum von α‐Fucosidase bewegen, führen zu einer geschlossenen Konformation des Komplexes mit Inhibitoren mit Ki‐Werten vom Mikro‐ bis zum Nanomolbereich. Bei Inhibitoren mit subnanomolaren Ki‐Werten treten zwar keine weiteren Konformationsänderungen in den beiden Schleifen auf, aber die Schleifen werden durch Wasserstoffbrücken und hydrophobe Wechselwirkungen weiter stabilisiert.

No abstract

No abstract

The cover picture shows the enzyme-inhibitor complex of a bacterial fucosidase derived from human microbiota. Fucose is implicated in many diseases, notably cancer and human fucosidosis, consequently there is evolving interest in the inhibition and manipulation of enzymes involved in fucose processing. 3D structural analysis complemented by kinetics and isothermal titration calorimetry paint a portrait of fucosidase inhibitor binding in which pH effects within the active centre (red) modify binding properties. Manipulation of "aglycon-mimicking" chemistries and inhibitor pK a values are likely routes to optimal fucosidase inhibition in the context of cellular and mechanistic probes and potential therapeutic agents. For more information see the communication by G. Davies et al. on p.