Journal
PLOS ONE
Volume 11, Issue 6, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0157509
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Funding
- global Takeda Pharmaceutical Company Limited
- Office of Science, Office of Basic Energy Sciences, Materials Sciences Division, of the U.S. Department of Energy at Lawrence Berkeley National Laboratory [DE-AC03-76SF00098]
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Trelagliptin (SYR-472), a novel dipeptidyl peptidase-4 inhibitor, shows sustained efficacy by once-weekly dosing in type 2 diabetes patients. In this study, we characterized in vitro properties of trelagliptin, which exhibited approximately 4-and 12-fold more potent inhibition against human dipeptidyl peptidase-4 than alogliptin and sitagliptin, respectively, and >10,000-fold selectivity over related proteases including dipeptidyl peptidase-8 and dipeptidyl peptidase-9. Kinetic analysis revealed reversible, competitive and slow-binding inhibition of dipeptidyl peptidase-4 by trelagliptin (t(1/2) for dissociation approximate to 30 minutes). X-ray diffraction data indicated a non-covalent interaction between dipeptidyl peptidase and trelagliptin. Taken together, potent dipeptidyl peptidase inhibitionmay partially contribute to sustained efficacy of trelagliptin.
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