Trelagliptin (SYR-472, Zafatek), Novel Once-Weekly Treatment for Type 2 Diabetes, Inhibits Dipeptidyl Peptidase-4 (DPP-4) via a Non-Covalent Mechanism.
Charles E GrimshawAndy JenningsRuhi KamranHikaru UenoNobuhiro NishigakiTakuo KosakaAkiyoshi TaniHiroki SanoYoshinobu KinugawaEmiko KoumuraLihong ShiKoji TakeuchiPublished in: PloS one (2016)
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 (t1/2 for dissociation ≈ 30 minutes). X-ray diffraction data indicated a non-covalent interaction between dipeptidyl peptidase and trelagliptin. Taken together, potent dipeptidyl peptidase inhibition may partially contribute to sustained efficacy of trelagliptin.
Keyphrases
- type diabetes
- end stage renal disease
- chronic kidney disease
- endothelial cells
- newly diagnosed
- ejection fraction
- cardiovascular disease
- glycemic control
- prognostic factors
- machine learning
- electronic health record
- peritoneal dialysis
- big data
- magnetic resonance imaging
- computed tomography
- combination therapy
- binding protein
- magnetic resonance
- weight loss
- mass spectrometry
- replacement therapy
- patient reported
- deep learning