The biology and therapeutic targeting of the proprotein convertases

Key Points The secretory proprotein convertases comprise a family of nine subtilisin-like serine proteases called proprotein convertase 1 (PC1), PC2, furin, PC4, PC5, paired basic amino acid cleaving enzyme 4 (PACE4), PC7, subtilisin kexin isozyme 1 (SKI-1; also known as S1P) and proprotein convertase subtilisin kexin 9 (PCSK9), and their genes have been named PCSK1 to PCSK9 . Knowledge gained from in vitro and ex vivo studies, as well as the characterization of the phenotypes of knockout mice and those associated with human mutations showed that these enzymes can have both redundant and unique physiological roles. Furin and PACE4 have a role in cancer and associated metastasis, in arthritis and in viral infections, which makes them attractive therapeutic targets. Small-molecule inhibitors, biologics or antisense silencing of these proprotein convertases are now being considered as therapeutic options. PC1 is implicated in obesity and type 2 diabetes, PC4 in reproduction and PC7 in the regulation of anxiety; these proprotein convertases are therefore attractive targets in these settings. Although SKI-1 has fundamental functions, such as the regulation of steroid and lipid synthesis, it also enhances viral infectivity, suggesting that the short-term use of pharmacological agents to block its activity could be beneficial. Hepatic PCSK9 is a major circulating protein that regulates the half-life of the low-density lipoprotein receptor (LDLR) as well as the very-low-density lipoprotein receptor (VLDLR). It is upregulated by statins and hence its inhibition (in combination with or without statins) is considered to be one of the most promising new treatment approaches to effectively lower levels of LDL-cholesterol. Multiple strategies are now in clinical trials (Phase I–III) to evaluate the efficacy and safety of blocking the function of PCSK9 and/or decrease its levels in the circulation. These include the use of monoclonal antibodies and adnectins, as well as antisense oligonucleotides and small-molecule inhibitors. The human proprotein convertases are a family of nine serine proteases that are involved in the processing and modulation of various proteins. Seidah and Prat review the physiological functions and pathological implications of proprotein convertases, highlighting recent advances and associated challenges in the development of novel therapeutics targeting them, including inhibitors of proprotein convertase subtilisin kexin 9 (PCSK9) for the treatmen