J Mol Med (2005) 83: 844–855 DOI 10.1007/s00109-005-0710-0 REVIEW Ajoy Basak Inhibitors of proprotein convertases Received: 30 November 2004 / Accepted: 6 July 2005 / Published online: 8 October 2005 # Springer-Verlag 2005 Abstract The discovery of mammalian subtilases, propro- tein convertases (PCs) or subtilisin-like proprotein con- vertases (SPCs), in 1990 was a result of sustained efforts in searching for enzyme/s responsible for maturation of in- active protein precursors. Since then, seven PCs have so far been discovered that cleave at the carboxy-terminal of a basic amino acid characterized by the consensus sequence Arg/Lys/His-X-X/Lys/Arg-Arg↓, where X denotes any amino acid other than Cys. Two additional PC subtypes— called subtilisin kexin isozyme 1 (SKI-1) or site 1 protease (S1P) and neural apoptosis regulated convertase 1 (NARC-1), also known as PCSK9—that cleave at the carboxy terminus of nonbasic amino acids were discovered later. Numerous studies revealed various important functional roles of PCs in health and diseases such as tumorigenesis, diabetes, viral infections, bacterial pathogenesis, atherosclerosis, and neu- rodegenarative diseases such as Alzheimer ’ s. Owing to these findings, PCs became a promising frontier for treat- ment of diverse pathologies. Thus modulation of PC activity with designed inhibitors is an attractive proposition not only for intervention of diseases, but also for biochemical char- acterization of these enzymes. Various physiological and bioengineered proteins as well as small molecules such as peptide, peptidomimetic, and nonpeptide compounds as inhibitors of PCs have been described in the literature. Among the strategies used for design of PC inhibitors, the most successful is the one based on bioengineered serpin proteins, of which the best example is α1-PDX, the double mutant variant of α1-antitrypsin (from A 355 IPM 358 to R 355 IPR 358 ). Others include small peptide inhibitors with C-terminal carboxyl function modified with a potent neu- cleophile or those containing pseudo or isosteric peptide bond at the scissile site of a suitable peptide substrate. Among nonpeptide PC inhibitors, the number is very limited. So far, these include 20-carbon atoms containing alicyclic diterpenes of andrographolide family and hetero- cyclic compounds that are ligands of Zn 2+ and Cu 2+ ions. Overall, these molecules display only a modest enzyme inhibition; however, they may serve as important lead structures for further development of more potent and specific nonpeptide PC inhibitors as potential therapeutic agents. Many PC inhibitors display their functional proper- ties in proliferation, fertilization, tumorigenesis, obesity, embryogenesis, or diabetes via their inhibitory action on PC activities. Keywords Proprotein convertases . Subtilisin proprotein convertases . Protease inhibitors . Antiproteolytic agents . Enzyme assay . Inhibition constant . Pseudopeptide . Serpin Introduction During past three decades, knowledge on the biosynthesis of functionally active polypeptides and proteins found in A. Basak (*) Regional Protein Chemistry Center, Diseases of Aging Program, Ottawa Health Research Institute, 725 Parkdale Ave, Ottawa, ON, K1Y 4E9, Canada e-mail: abasak@ohri.ca Tel.: +1-613-7985555 Fax: +1-613-7614355 AJOY BASAK received his Ph.D. in Organic Natural Product Chemistry from the University of Cal- cutta, India. After training in MIT, USA, he joined Bioor- ganic Chemistry, U. Montreal, Canada. He is currently a Scientist at the Ottawa Health Research Institute and an Assistant Professor, Biochem- istry, Microbiology and Im- munology, University of Ottawa. His research interests include proprotein conver- tases, their function and reg- ulators: design of inhibitors, delivery and biochemical applications.