Inhibitors and Activity-Based Probes for Human A-Amylase

PS1 Poster session 1 Odd numbers
Location (hall): 
Start/end time: 
Monday, July 1, 2019 - 15:45 to 17:15

Yurong Chen1

1Leiden Institute Of Chemistry, Leiden University, Leiden, The Netherlands

Type 2 diabetes mellitus is a metabolic disorder that affects millions of people worldwide. Among the oral anti-diabetic drugs used in the clinic are α-glucosidase inhibitors, which prevent hyperglycosemia by slowing digestion of starch and malto-oligosaccharides in the gut.[1] Unfortunately, the use of these drugs often results in severe gastrointestinal side effects. Partial hydrolysis of starch is accomplished by salivary α-amylase, with principal cleavage provided by human pancreatic α-amylase (HPA) within the gut, generating linear and branched malto-oligosaccharides.[2] Selective inhibitors targeting exclusively HPA, the first enzyme in the digestion cascade, would be of interest, since side effects that arise from inhibition of other α-glucosidases would be avoided.[3] One attractive approach, envisaged here, would be the design of such selective irreversible inhibitors and activity-based probes (ABPs) by the use of epoxide, aziridine and cyclosulfate as electrophilic traps.[4]

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  2. G. D. Brayer, G. Sidhu, R. Maurus, E. H. Rydberg, C. Braun, Y.-L. Wang, N. T. Nguyen, C. M. Overall, S. G. Withers, Biochemistry 2000, 39, 4778−4791.
  3. S. Caner, X. Zhang, J. Jiang, H.-M. Chen, N. T. Nguyen, H. S. Overkleeft, G. D. Brayer, S. G. Withers, FEBS Letters 2016, 590, 1143-1151.
  4. M. Artola, L. Wu, M. J. Ferraz, C. L. Kuo, L. Raich, I. Z. Breen, W. A. Offen, J. D. C. Codée, G. A. Van Der Marel, C. Rovira, M. F. G. Aerts, G. J. Davies, H. S. Overkleeft, ACS Cent. Sci. 2017, 3, 784–793.