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Published on: December 20, 2017
A double-headed cathepsin B inhibitor devoid of warhead
Patricia Schenker1, Pietro Alfarano, Peter Kolb
1Department of Biochemistry, University of Zurich, CH-8057 Zurich, Switzerland.
Protein Science : a Publication of the Protein Society
|September 18, 2008
Summary
Researchers identified a novel inhibitor targeting the occluding loop of human cathepsin B, a cysteine peptidase. This inhibitor modulates enzyme activity by stabilizing the loop, offering a new strategy for therapeutic development.
Area of Science:
- Biochemistry
- Enzyme Inhibition
- Drug Discovery
Background:
- Most peptidase inhibitors target the active site.
- Cathepsin B possesses a unique occluding loop that regulates its endo- and exopeptidase activity.
- Targeting this loop offers a novel inhibition strategy.
Purpose of the Study:
- To identify inhibitors that modulate human cathepsin B activity by interacting with its occluding loop.
- To develop inhibitors that do not rely on covalent modification of catalytic residues.
Main Methods:
- High-throughput docking procedure to screen compounds.
- In silico approach to identify potential inhibitors.
- Kinetic analysis to determine the mechanism of inhibition.
Main Results:
- Identified [2-[2-(2,4-dioxo-1,3-thiazolidin-3-yl)ethylamino]-2-oxoethyl] 2-(furan-2-carbonylamino) acetate as a reversible, double-headed competitive inhibitor.
- The inhibitor stabilizes the occluding loop in its closed conformation, reducing endopeptidase activity.
- The inhibitor also hinders substrate binding at the C-terminus, inhibiting exopeptidase activity.
Conclusions:
- The identified compound effectively inhibits both endo- and exopeptidase activities of cathepsin B.
- Targeting the occluding loop provides a novel therapeutic strategy for diseases involving cathepsin B.
- This approach offers a non-covalent, selective inhibition mechanism.
