Abstract
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, WeinheimRetaining glycosidases are an important class of enzymes involved in glycan degradation. To study better the role of specific enzymes in deglycosylation processes, and thereby the importance of particular glycosylation patterns, a set of potent inhibitors, each specific to a particular glycosidase, would be an invaluable toolkit. Towards this goal, we detail here a more in-depth study of a prototypical macrocyclic peptide inhibitor of the model retaining glycosidase human pancreatic α-amylase (HPA). Notably, incorporation of l-DOPA into this peptide affords an inhibitor of HPA with potency that is tenfold higher (Ki=480 pm) than that of the previously found consensus sequence. This represents a first successful step in converting a recently discovered natural-product-derived motif, already specific for the catalytic side-chain arrangement conserved in the active sites of retaining glycosidases, into a tuneable retaining glycosidase inhibition warhead.
| Original language | English |
|---|---|
| Pages (from-to) | 2333-2339 |
| Journal | ChemBioChem |
| Volume | 18 |
| Issue number | 23 |
| DOIs | |
| Publication status | Published - 5 Dec 2017 |
| Externally published | Yes |
Funding
We would like to thank Prof. Stephen G. Withers (University of British Columbia) for kindly providing deglycosylated recombinant human pancreatic a-amylase and 2-chloro-4-nitrophenyl-ad-maltotrioside, Dr. John Kruijtzer (Utrecht University) for assis- tance with peptide synthesis, and Utrecht University for financial support.
| Funders | Funder number |
|---|---|
| Universiteit Utrecht | |
| University of British Columbia |