Synthesis and biological evaluation of a chitobiose-based peptide N-glycanase inhibitor library.
Peptide N-glycanase (PNGase), the enzyme responsible for the deglycosylation of N-linked glycoproteins, has an active site related to that of cysteine proteases. Chitiobiose was equipped with electrophilic traps often used in cysteine protease inhibitors, and the resulting compounds were evaluated as PNGase inhibitors. We found that the electrophilic trap of the inhibitor has a great influence on the potency of the compounds with the chloromethyl ketone inhibitor being the first potent C-glycoside-based PNGase inhibitor.
Witte
Martin D
MD
Leiden Institute of Chemistry, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
Horst
Danielle
D
Wiertz
Emmanuel J H J
EJ
van der Marel
Gijsbert A
GA
Overkleeft
Herman S
HS
D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry; D004187:Disaccharides / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013379:Substrate Specificity
D000081:Acetamides; D015853:Cysteine Proteinase Inhibitors; D004187:Disaccharides; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; C032438:chitobiose; C030686:acetamide; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase