NWO ChemThem grant for Hermen Overkleeft


Hermen Overkleeft and Hans Aerts (AMC) received a NWO ChemThem grant for their proposal "Chemical biology of glucosylceramide metabolism: fundamental studies and clinical applications for Gaucher disease"

With this proposal they aim to develop chemical biology tools and approaches to understand, and interfere with, glucosylceramide metabolism in relation to the lysosomal storage disorder, Gaucher disease. Glucosylceramide metabolism in man, and the enzymes known to be involved, is summarized in Figure 1. Gaucher patients are characterized by a genetic deficiency in the lysosomal hydrolase, GBA1, resulting in the accumulation of glucosylceramide. Levels of this glycolipid can be therapeutically corrected by either enzyme replacement therapy (administration of recombinant GBA1) or substrate reduction therapy (administration of GCS inhibitors). A third clinical approach currently under investigation is chemical chaperone therapy, aimed at stabilizing the proper fold of nascent, mutant GBA1 forms in the endoplasmic reticulum so that more copies of functional enzymes reach lysosomal compartments, thereby increasing residual lysosomal enzyme activity.

The underlying proposal builds on several discoveries we recently made and that pertain glucosylceramide metabolism. We developed a set of activity-based probes with which endogenous retaining β-glucosidases could for the first time and with high efficiency be monitored in living cells. Our set of probes includes a cyclophellitol derivative with which GBA1 can be detected in healthy and Gaucher cells at pH 4-5, that is, in lysosomal environments where GBA1 activity is required. A corresponding aziridine derivative labels retaining β-glucosidase activity in general and reacts with GBA1 also at neutral pH, and thus also in the endoplasmic reticulum. We here propose three research lines, each of which can be executed independently but that are interconnected both with respect to the underlying biology and the nature of the approach taken, namely that of activity-based protein profiling as an enabling strategy in chemical biology research.