Pro-protein convertase subtilisin/kexin type 9 (PCSK9) is a secreted serin protease that plays a very important role in low density lipoproteins (LDL) metabolism. Once secreted, PCSK9 binds LDL receptors (LDLRs), targeting them toward intracellular degradation through an endosomal/lysosomal route. Inhibition of PCSK9 can reduce LDLRs degradation and increase the expression of LDLRs in the cell surface, resulting in an enhanced recycling of LDLRs and a reduction in the levels of LDL cholesterol. Hence, inhibitors of PCSK9 suppose a promising therapeutic strategy for the treatment of hypercholesterolemia.

Discovery of PCSK9

PCSK9 was first described as neural apoptosis-regulated convertase 1 (NARC-1) in studies of cerebral neuron apoptosis, suggesting that it could be implicated in the differentiation of cortical neurons ^[1]. Concomitant and following studies in patients with familiar hypercholesterolemia revealed the clinical importance of PCSK9, showing that patients with gain-of-function mutations presented increased levels of cholesterol in plasma (i.e. hypercholesterolemia) due to reduced expression of LDLRs. In contrast, loss-of-function variants of PSCK9 are associated with a reduction of LDL cholesterol levels and a lower risk of cardiovascular disease. The role of PSCK9 in LDLRs and cholesterol metabolism has been confirmed in animal models. Thus, mice overexpressing PCSK9 show a reduction in the expression of hepatic LDLRs and hypercholesterolemia, whereas knockout mice for PCSK9 present decreased levels of plasmatic LDL cholesterol because of increased levels of LDLRs ^[2][3].

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Disease

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Structural highlights

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