An article just published in Endocrine Reviews 2025 offers a fascinating overview of the discoveries made by Dr. Nabil G. Seidah's laboratory at the IRCM, in relation to the properties of proprotein convertases.
From left to right: Nabil G. Seidah and Vatsal Sachan
Proprotein convertases are a family of nine secretory enzymes (proteases related to bacterial Subtilisin and yeast Kexin, known by the acronyms PCSK1 to PCSK9) responsible for the activation or inactivation of multiple proteins in the genome. Director of the Biochemical Neuroendocrinology Research Unit at IRCM, Dr. Nabil G. Seidah and his team have successfully identified and cloned 7 of 9 known convertases. In addition, they have participated in the characterization of the physiological and pathological functions of all members of the PCSK family.
The identification of PCSK9 (the 9th member of the family) at the IRCM in 2003 was a landmark discovery, particularly following the genetic proof, carried out in collaboration with a Parisian team led by Dr. Catherine Boileau, which demonstrated its non-enzymatic involvement in cholesterol regulation. In the wake of these advances, PCSK9 inhibitors were developed and are now prescribed worldwide, mainly to lower plasma cholesterol to levels of -50 to -60%, far lower than those achieved by “statins” (a highly prescribed clinical drug) alone; Not to mention the fact that PCSK9 inhibitors have demonstrated remarkable anti-inflammatory properties.
In the Seidah laboratory, the recent publication by Vatsal Sachan (PhD) and colleagues, of an unusual new role for PCSK7 (the 7th member of the family) was a revelation, as it opened the door to the identification of new non-enzymatic functions for PCSK7, acting as a molecular chaperone for apolipoprotein B (apoB). This discovery enabled the development of an antisense oligonucleotide (ASO) treatment in animal models, leading to effective regression of hepatic steatosis, fibrosis and inflammation induced by a diet rich in fat, cholesterol and fructose.
Hepatic steatosis affects between 25 and 30% of humans worldwide. No drug is currently known to be truly effective against this multifactorial scourge.
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The discovery of a molecular chaperone function for PCSK7 complements that of PCSK9. The combination of PCSK7 and PCSK9 inhibitors is therefore proposed for the treatment of cardiovascular and inflammatory diseases, as well as cancer and associated metastases.
The article just published in Endocrine Reviews, which complements the PCSK9 article published in 2023, traces the history of these discoveries, as well as the physiological properties and pathologies associated with deregulation of PCSK7 expression. Indeed, it turns out that PCSK7 may act as a molecular chaperone for other proteins involved in cancer and inflammation. We predict that, in the near future, therapeutic approaches involving PCSK7 inhibitors in certain cardiovascular diseases could be validated in several inflammatory pathologies and in cancer.
Follow-up to this work
The discoveries of PCSK7 and PCSK9 have clearly opened up several new possibilities for clinical therapeutic strategies to combat prevalent pathologies in our societies. The definition of the other functions of these convertases, and especially the advantage of combining PCSK7 and PCSK9 inhibitors, should be advocated and applied more widely in clinic. Validation of these new preclinical therapeutic approaches is essential in a variety of animal models, and ultimately in the human clinical phase.
Dr. Seidah thanks all the members of his laboratory, including Anna Roubtsova, Mailys Le Dévéhat, Alexandra Evagelidis, Drs. Rachid Essalmani, Delia Susan-Resiga, and Annik Prat. He also highlights the essential collaboration of Drs. Martin Sauvageau and Robert Scott Kiss.
References
1. Seidah NG, Prat A. The biology and therapeutic targeting of the proprotein convertases. Nat Rev Drug Discov 11, 367-383 (2012).
2. Seidah NG, et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proceedings of the National Academy of Sciences of the United States of America 100, 928-933 (2003).
3. Abifadel M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nature Genetics 34, 154-156 (2003).
4. Benjannet S, et al. NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. Journal of Biological Chemistry 279, 48865-48875 (2004).
5. Seidah NG, Prat A. The Multifaceted Biology of PCSK9. Endocr Rev 43, 558-582 (2022).
6. Sachan V, Susan-Resiga D, Lam K, Seidah NG. The Biology and Clinical Implications of PCSK7. Endocr Rev 46, 281-299 (2025).
