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Synthetic small-molecule prohormone convertase 2 inhibitors
Dorota Kowalska1, Jin Liu, Jon R Appel
1Department of Anatomy and Neurobiology, University of Maryland at Baltimore, Baltimore, Maryland 21201, USA.
Molecular Pharmacology
|December 17, 2008
Summary
Researchers identified novel small-molecule inhibitors for prohormone convertase 2 (PC2), a key enzyme in peptide hormone maturation. Pyrrolidine bis-piperazines and bicyclic guanidines show promise for developing new PC2-targeted therapies.
Area of Science:
- Biochemistry
- Enzymology
- Drug Discovery
Background:
- Proprotein convertases (PCs) are crucial for maturing peptide hormones.
- While furin inhibitors exist, specific inhibitors for prohormone convertase 1/3 (PC1/3) and prohormone convertase 2 (PC2) are lacking.
Purpose of the Study:
- To identify and characterize novel small-molecule inhibitors targeting PC2.
- To explore potential therapeutic applications of PC2 inhibitors.
Main Methods:
- Screening of 38 small-molecule positional scanning libraries against recombinant mouse PC2.
- Design and testing of individual compounds from identified chemical scaffolds (bicyclic guanidines and pyrrolidine bis-piperazines).
- Kinetic analysis to determine inhibition type and potency (K(i) values).
Main Results:
- Two scaffolds, bicyclic guanidines and pyrrolidine bis-piperazines, were identified as promising PC2 inhibitors.
- Pyrrolidine bis-piperazines demonstrated irreversible, noncompetitive inhibition with a potent K(i) of 0.54 microM.
- Bicyclic guanidines showed a K(i) of 3.3 microM, with limited cross-reactivity (<25 microM for PC1/3 or furin).
Conclusions:
- Bicyclic guanidines and pyrrolidine bis-piperazines represent valuable starting points for developing selective PC2 inhibitors.
- PC2 inhibitors could be used to block PC2-dependent processes like glucagon production and treat conditions such as small-cell carcinoma.
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