Targeting Enteropeptidase with Reversible Covalent Inhibitors To Achieve Metabolic Benefits
Weimei Sun1, Xuqing Zhang2, Maxwell D Cummings2
1DPDS Discovery Technology and Molecular Pharmacology, Spring House, Pennsylvania (W.S., M.W., R.A.); DPDS Analytical Sciences, La Jolla, California (J.W.); Discovery Chemistry, Spring House, Pennsylvania (X.Z., M.D.C., B.Z., Y.Z., J.La.); CVM Discovery, Spring House, Pennsylvania (K.A., J.Leo., J.Len.); and Janssen Research & Development, LLC, Spring House, Pennsylvania wsun5@its.jnj.com.
The Journal of Pharmacology and Experimental Therapeutics
|October 9, 2020
Summary
Camostat is a potent, reversible covalent inhibitor of enteropeptidase (EP), a target for metabolic diseases. Its mechanism and kinetics are key for developing effective chemotherapeutics for conditions like obesity and diabetes.
Area of Science:
- Biochemistry
- Pharmacology
- Drug Discovery
Background:
- Enteropeptidase (EP) inhibition is a novel therapeutic strategy for metabolic diseases.
- Camostat, a known drug, has shown clinical efficacy, but its precise mechanism of EP inhibition was unclear.
Purpose of the Study:
- To elucidate the mechanism and kinetics of camostat's inhibition of enteropeptidase (EP).
- To establish the therapeutic potential of reversible covalent EP inhibitors for metabolic diseases.
Main Methods:
- Utilized high-resolution liquid chromatography-mass spectrometry (LC-MS) to identify covalent adducts.
- Determined inhibition potency (k_inact/K_I) and enzyme reactivation half-life.
- Resolved a crystal structure of EP with a camostat analog to visualize the binding site.
Main Results:
- Camostat is a potent reversible covalent inhibitor of EP (k_inact/K_I = 1.5 × 10^4 M^-1s^-1).
- LC-MS and crystal structure confirmed covalent modification of EP's catalytic serine.
- Inhibition is reversible with a 14.3-hour half-life; structural modifications impact inhibitory mechanisms.
Conclusions:
- Reversible covalent inhibition of EP by camostat is a viable therapeutic approach for metabolic diseases.
- Mechanistic and kinetic characterization is crucial for optimizing drug design and clinical efficacy.
- EP is a validated drug target for treating obesity, diabetes, and related metabolic disorders.
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