TY - JOUR
T1 - Discovery of Mechanism-Based Inactivators for Human Pancreatic Carboxypeptidase A from a Focused Synthetic Library
AU - Testero, Sebastián A.
AU - Granados, Carla
AU - Fernández, Daniel
AU - Gallego, Pablo
AU - Covaleda, Giovanni
AU - Reverter, David
AU - Vendrell, Josep
AU - Avilés, Francesc X.
AU - Pallarès, Irantzu
AU - Mobashery, Shahriar
PY - 2017/10/12
Y1 - 2017/10/12
N2 - © 2017 American Chemical Society. Metallocarboxypeptidases (MCPs) are involved in many biological processes such as fibrinolysis or inflammation, development, Alzheimer's disease, and various types of cancer. We describe the synthesis and kinetic characterization of a focused library of 22 thiirane- and oxirane-based potential mechanism-based inhibitors, which led to discovery of an inhibitor for the human pro-carboxypeptidase A1. Our structural analyses show that the thiirane-based small-molecule inhibitor penetrates the barrier of the pro-domain to bind within the active site. This binding leads to a chemical reaction that covalently modifies the catalytic Glu270. These results highlight the importance of combined structural, biophysical, and biochemical evaluation of inhibitors in design strategies for the development of spectroscopically nonsilent probes as effective beacons for in vitro, in cellulo, and/or in vivo localization in clinical and industrial applications.
AB - © 2017 American Chemical Society. Metallocarboxypeptidases (MCPs) are involved in many biological processes such as fibrinolysis or inflammation, development, Alzheimer's disease, and various types of cancer. We describe the synthesis and kinetic characterization of a focused library of 22 thiirane- and oxirane-based potential mechanism-based inhibitors, which led to discovery of an inhibitor for the human pro-carboxypeptidase A1. Our structural analyses show that the thiirane-based small-molecule inhibitor penetrates the barrier of the pro-domain to bind within the active site. This binding leads to a chemical reaction that covalently modifies the catalytic Glu270. These results highlight the importance of combined structural, biophysical, and biochemical evaluation of inhibitors in design strategies for the development of spectroscopically nonsilent probes as effective beacons for in vitro, in cellulo, and/or in vivo localization in clinical and industrial applications.
KW - Carboxypeptidase A
KW - X-ray crystallography
KW - mechanism-based inactivators
KW - thiiranes
U2 - 10.1021/acsmedchemlett.7b00346
DO - 10.1021/acsmedchemlett.7b00346
M3 - Article
VL - 8
SP - 1122
EP - 1127
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
SN - 1948-5875
IS - 10
ER -