Development and functional analysis of novel PCSK9/LDLR interaction inhibitors for hypercholesterolemia treatment
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Abstract:
Hypercholesterolemia characterized by excessively elevated levels of plasma low-density lipoprotein-cholesterol (LDLc) increases the risk of atherosclerosis, causing cardiovascular disease and cerebrovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9), which is secreted from liver, interacts with LDL-receptor (LDLR) that uptakes LDLc from plasma into hepatocytes. The PCSK9-LDLR interaction leads degradation of the LDLR on hepatocytes, resulting in elevation of plasma LDLc levels. Although anti-PCSK9 antibodies that inhibit PCSK9-LDLR interaction have been used for the treatment of hypercholesterolemia, the antibody agents are very expensive because they are produced using mammalian cells. To overcome this problem, it is necessary to develop PCSK9/LDLR interaction inhibitors that are produced by chemical synthesis to be low-cost in hypercholesterolemia treatment.Keywords:
PCSK9
Kexin
Proprotein Convertases
Low-density lipoprotein
Proprotein Convertases
Proprotein convertase subtilisin/kexin 9 (PCSK9) is a proteinase K subtype of mammalian subtilases collectively called PCSKs. PCSK9 upregulates plasma-cholesterol level by degrading low-density lipoprotein receptor (LDL-R). As a result, PCSK9 is a major target for intervention of hypercholesterolemia and in this regard PCSK9- inhibitors may find useful therapeutic and biochemical applications.Our objective is to develop short peptide based PCSK9 inhibitors from its own pro and/or catalytic domains.Using human (h) hepatic HepG2 and Huh7 cells we showed that the acidic N-terminal hPCSK(931-60), 31-40 and the mid-basic hPCSK(991-120) peptides derived from hPCSK9-prodomain significantly enhanced LDL-R level without altering PCSK9 content. Moreover, the physiologically relevant phoshpho-Ser47 and sulpho-Y38 containing hPCSK(931-60) peptides diminished LDL-R level suggesting that such posttranslational modifications in the prodomain lead to gain of PCSK9- functional activity. These modifications are thus expected to lead to even higher level of plasma cholesterol. As expected, addition of purified recombinant-PCSK9 to the culture medium decreased LDL-R level which can be restored back by exogenous addition of hPCSK(931-40), (31-60) or (91-120) peptides. Using a series of truncated peptides, we identified the most potent LDL-R promoting activity to reside within the prodomain sequence hPCSK(931-37). Two catalytic domain peptides hPCSK(9181-200) and hPCSK(9368-390), containing proposed LDL-R interacting sites have been shown to diminish LDL-R level.Our study concludes that specific peptides from pro- and catalytic domains of hPCSK9 can regulate LDL-R in cell based assay and may be useful for development of novel therapeutics for cholesterol regulation.
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Proprotein convertase subtilisin/kexin type 9 (PCSK9) has gained extensive attention since the discovery of its role in mediating hepatic low-density lipoprotein (LDL)-receptor (LDLR) degradation, and therefore regulating plasma LDL cholesterol clearance. However, emerging studies have indicated that PCSK9 may have pleiotropic effects on the development of atherosclerosis and eventually cardiac dysfunction by mechanisms independent of the regulation of LDL cholesterol levels. In this review, we will discuss recent findings of how PCSK9 affects cellular responses and the pro-inflammatory microenvironment within the local atherosclerotic vascular wall, which are critical for atherosclerotic plaque progression. We will also discuss recent research on the potential direct effects of PCSK9 on cardiomyocyte viability and function. These pathways may be critical for understanding the mechanisms of PCSK9’s cardioprotective effects beyond LDL cholesterol lowering.
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Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor is a powerful low density lipoprotein cholesterol (LDL-C)-lowering therapy, but this drug is expensive. This study aimed to describe the real-world treatment conditions in patients initiating PCSK9 inhibitor in Taiwan.
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Proprotein Convertases
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Autosomal dominant familial hypercholesterolemia (FH) affects approximately 1/250 individuals and potentially leads to elevated blood cholesterol and a significantly increased risk of atherosclerosis. Along with improvements in detection and the increased early diagnosis and treatment, the serious burden of FH on families and society has become increasingly apparent. Since FH is strongly associated with proprotein convertase subtilisin/kexin type 9 (PCSK9), increasing numbers of studies have focused on finding effective diagnostic and therapeutic methods based on PCSK9. At present, as PCSK9 is one of the main pathogenic FH genes, its contribution to FH deserves more explorative research.
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Proprotein Convertases
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The secretory proprotein convertase (PC) family comprises nine members, as follows: PC1/3, PC2, furin, PC4, PC5/6, paired basic amino acid cleaving enzyme 4, PC7, subtilisin kexin isozyme 1/site 1 protease (SKI-1/S1P), and PC subtilisin/kexin type 9 (PCSK9). The first seven PCs cleave their substrates at single/paired basic residues and exhibit specific and often essential functions during development and/or in adulthood. The essential SKI-1/S1P cleaves membrane-bound transcription factors at nonbasic residues. In contrast, PCSK9 cleaves itself once, and the secreted inactive protease drags the low-density lipoprotein receptors (LDLR) and very LDLR (VLDLR) to endosomal/lysosomal degradation. Inhibitory PCSK9 monoclonal antibodies are now prescribed to treat hypercholesterolemia. This review focuses on the implication of PCs in cardiovascular functions and diseases, with a major emphasis on PCSK9. We present a phylogeny of the PCs and the analysis of PCSK9 haplotypes in modern and archaic human species. The absence of PCSK9 in mice led to the discovery of a sex- and tissue-specific subcellular distribution of the LDLR and VLDLR. PCSK9 inhibition may have other applications because it reduces inflammation and sepsis in a LDLR-dependent manner. Our present understanding of the cellular mechanism(s) that enables PCSK9 to induce the degradation of receptors is reviewed, as well as the consequences of its key natural mutations. The PCSK9 ongoing clinical trials are reviewed. Finally, how the other PCs may impact cardiovascular disease and the metabolic syndrome, and become relevant targets, is discussed.
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