Trelagliptin (SYR-472, Zafatek), novel once-weekly treatment for type 2 diabetes, inhibits dipeptidyl peptidase-4 (DPP-4) via a non-covalent mechanism
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. Altogether, potent dipeptidyl peptidase inhibitionmay partially contribute to sustained efficacy of trelagliptin.
- Authors:
-
- Takeda California Inc., San Diego, CA (United States). Enzymology and Biophysical Chemistry
- Takeda California Inc., San Diego, CA (United States). Computational Sciences and Crystallography
- Takeda Pharmaceutical Co. Ltd., Fujisawa, Kanagawa (Japan). Cardiovascular and Metabolic Drug Discovery Unit, Pharmaceutical Research Division
- Takeda Pharmaceutical Co. Ltd., Fujisawa, Kanagawa (Japan). Bio-Molecular Research Laboratories, Pharmaceutical Research Division
- Takeda Pharmaceutical Co. Ltd., Osaka (Japan). Takeda Development Center Japan
- Publication Date:
- Research Org.:
- Takeda California Inc., San Diego, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES)
- OSTI Identifier:
- 1285963
- Grant/Contract Number:
- AC03-76SF00098
- Resource Type:
- Accepted Manuscript
- Journal Name:
- PLoS ONE
- Additional Journal Information:
- Journal Volume: 11; Journal Issue: 6; Journal ID: ISSN 1932-6203
- Publisher:
- Public Library of Science
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; double-blind; iv; alogliptin; complex; potent; discovery; profiles; rats; blood plasma; crystal structure; dogs; type 2 diabetes; chemical dissociation; diabetes mellitus; proteases; enzyme inhibitors
Citation Formats
Grimshaw, Charles E., Jennings, Andy, Kamran, Ruhi, Ueno, Hikaru, Nishigaki, Nobuhiro, Kosaka, Takuo, Tani, Akiyoshi, Sano, Hiroki, Kinugawa, Yoshinobu, Koumura, Emiko, Shi, Lihong, and Takeuchi, Koji. Trelagliptin (SYR-472, Zafatek), novel once-weekly treatment for type 2 diabetes, inhibits dipeptidyl peptidase-4 (DPP-4) via a non-covalent mechanism. United States: N. p., 2016.
Web. doi:10.1371/journal.pone.0157509.
Grimshaw, Charles E., Jennings, Andy, Kamran, Ruhi, Ueno, Hikaru, Nishigaki, Nobuhiro, Kosaka, Takuo, Tani, Akiyoshi, Sano, Hiroki, Kinugawa, Yoshinobu, Koumura, Emiko, Shi, Lihong, & Takeuchi, Koji. Trelagliptin (SYR-472, Zafatek), novel once-weekly treatment for type 2 diabetes, inhibits dipeptidyl peptidase-4 (DPP-4) via a non-covalent mechanism. United States. https://doi.org/10.1371/journal.pone.0157509
Grimshaw, Charles E., Jennings, Andy, Kamran, Ruhi, Ueno, Hikaru, Nishigaki, Nobuhiro, Kosaka, Takuo, Tani, Akiyoshi, Sano, Hiroki, Kinugawa, Yoshinobu, Koumura, Emiko, Shi, Lihong, and Takeuchi, Koji. Tue .
"Trelagliptin (SYR-472, Zafatek), novel once-weekly treatment for type 2 diabetes, inhibits dipeptidyl peptidase-4 (DPP-4) via a non-covalent mechanism". United States. https://doi.org/10.1371/journal.pone.0157509. https://www.osti.gov/servlets/purl/1285963.
@article{osti_1285963,
title = {Trelagliptin (SYR-472, Zafatek), novel once-weekly treatment for type 2 diabetes, inhibits dipeptidyl peptidase-4 (DPP-4) via a non-covalent mechanism},
author = {Grimshaw, Charles E. and Jennings, Andy and Kamran, Ruhi and Ueno, Hikaru and Nishigaki, Nobuhiro and Kosaka, Takuo and Tani, Akiyoshi and Sano, Hiroki and Kinugawa, Yoshinobu and Koumura, Emiko and Shi, Lihong and Takeuchi, Koji},
abstractNote = {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. Altogether, potent dipeptidyl peptidase inhibitionmay partially contribute to sustained efficacy of trelagliptin.},
doi = {10.1371/journal.pone.0157509},
journal = {PLoS ONE},
number = 6,
volume = 11,
place = {United States},
year = {Tue Jun 21 00:00:00 EDT 2016},
month = {Tue Jun 21 00:00:00 EDT 2016}
}
Web of Science
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