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Synthetic Small-Molecule Prohormone Convertase 2 Inhibitors

Department of Anatomy and Neurobiology, University of Maryland at Baltimore, Baltimore, Maryland (D.K., J.L., A.O., I.L.); Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, Nebraska (R.B.M.); and the Torrey Pines Institute for Molecular Studies, San Diego, California (J.R.A., A.N., R.A.H.)

The proprotein convertases are believed to be responsible for the proteolytic maturation of a large number of peptide hormone precursors. Although potent furin inhibitors have been identified, thus far, no small-molecule prohormone convertase 1/3 or prohormone convertase 2 (PC2) inhibitors have been described. After screening 38 small-molecule positional scanning libraries against recombinant mouse PC2, two promising chemical scaffolds were identified: bicyclic guanidines, and pyrrolidine bis-piperazines. A set of individual compounds was designed from each library and tested against PC2. Pyrrolidine bis-piperazines were irreversible, time-dependent inhibitors of PC2, exhibiting noncompetitive inhibition kinetics; the most potent inhibitor exhibited a K_i value for PC2 of 0.54 µM. In contrast, the most potent bicyclic guanidine inhibitor exhibited a K_i value of 3.3 µM. Cross-reactivity with other convertases was limited: pyrrolidine bis-piperazines exhibited K_i values greater than 25 µM for PC1/3 or furin, whereas the K_i values of bicyclic guanidines for these other convertases were more than 15 µM. We conclude that pyrrolidine bis-piperazines and bicyclic guanidines represent promising initial leads for the optimization of therapeutically active PC2 inhibitors. PC2-specific inhibitors may be useful in the pharmacological blockade of PC2-dependent cleavage events, such as glucagon production in the pancreas and ectopic peptide production in small-cell carcinoma, and to study PC2-dependent proteolytic events, such as opioid peptide production.

Received for publication August 14, 2008.

Accepted for publication December 10, 2008.

Address correspondence to: Dr. Iris Lindberg, Dept. of Department of Anatomy and Neurobiology, University of Maryland Baltimore, 20 Penn St., HSFII, S251, Baltimore, MD 21201. E-mail: ilind001{at}umaryland.edu