2. Academic Validation
  3. Trelagliptin (SYR-472, Zafatek), Novel Once-Weekly Treatment for Type 2 Diabetes, Inhibits Dipeptidyl Peptidase-4 (DPP-4) via a Non-Covalent Mechanism

Trelagliptin (SYR-472, Zafatek), Novel Once-Weekly Treatment for Type 2 Diabetes, Inhibits Dipeptidyl Peptidase-4 (DPP-4) via a Non-Covalent Mechanism

  • PLoS One. 2016 Jun 21;11(6):e0157509. doi: 10.1371/journal.pone.0157509.
Charles E Grimshaw 1,  Andy Jennings 2,  Ruhi Kamran 1,  Hikaru Ueno 3,  Nobuhiro Nishigaki 3,  Takuo Kosaka 4,  Akiyoshi Tani 4,  Hiroki Sano 5,  Yoshinobu Kinugawa 5,  Emiko Koumura 5,  Lihong Shi 1,  Koji Takeuchi 3
Affiliations

Affiliations

  • 1 Enzymology and Biophysical Chemistry, Takeda California, Inc., San Diego, California, United States of America.
  • 2 Computational Sciences and Crystallography, Takeda California, Inc., San Diego, California, United States of America.
  • 3 Cardiovascular and Metabolic Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
  • 4 Bio-Molecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
  • 5 Takeda Development Center Japan, Takeda Pharmaceutical Company Limited, Osaka, Japan.
PMID: 27328054 DOI: 10.1371/journal.pone.0157509
Abstract

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.

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