title: Synthetic small-molecule prohormone convertase 2 inhibitors.
abstract: 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 microM. In contrast, the most potent bicyclic guanidine inhibitor exhibited a K(i) value of 3.3 microM. Cross-reactivity with other convertases was limited: pyrrolidine bis-piperazines exhibited K(i) values greater than 25 microM for PC1/3 or furin, whereas the K(i) values of bicyclic guanidines for these other convertases were more than 15 microM. 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.
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland at Baltimore, Baltimore, Maryland 21201, USA.
authors.forename: Dorota
authors.initials: D
authors.lastname: Kowalska
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.forename: Jon R
authors.initials: JR
authors.lastname: Appel
authors.forename: Akihiko
authors.initials: A
authors.lastname: Ozawa
authors.forename: Adel
authors.initials: A
authors.lastname: Nefzi
authors.forename: Robert B
authors.initials: RB
authors.lastname: Mackin
authors.forename: Richard A
authors.initials: RA
authors.lastname: Houghten
authors.forename: Iris
authors.initials: I
authors.lastname: Lindberg
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006146:Guanidines / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D051379:Mice; D045706:Proprotein Convertase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D006146:Guanidines; D011480:Protease Inhibitors; D011759:Pyrrolidines; D045706:Proprotein Convertase 2