1. Towards Tuneable Retaining Glycosidase-Inhibiting Peptides by Mimicry of a Plant Flavonol Warhead.
- Author
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Yoshisada R, van Gijzel L, and Jongkees SAK
- Subjects
- Amino Acid Sequence, Binding Sites, Catalytic Domain, Circular Dichroism, Enzyme Inhibitors chemistry, Flavones chemistry, Humans, Kinetics, Levodopa chemistry, Molecular Dynamics Simulation, Pancreatic alpha-Amylases antagonists & inhibitors, Peptides chemistry, Plants metabolism, Trisaccharides chemistry, Enzyme Inhibitors metabolism, Flavonols chemistry, Pancreatic alpha-Amylases metabolism, Peptides metabolism, Plants chemistry
- Abstract
Retaining 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 (K
i =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., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)- Published
- 2017
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