Proprotein Convertase Subtilisin/kexin Type 9 Activity Research Articles

Natural Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors: A Review.

PCSK9 (proprotein convertase subtilisin/kexin type 9) is an enzyme that helps to reduce cardiovascular events. This clinical result is attributable primarily to the crucial involvement of PCSK9 in regulating the low-density lipoprotein cholesterol level. Because oral anti-PCSK9 medications have yet to be available, the benefits of this unique treatment approach have been diminished. Identifying naturally occurring PCSK9 inhibitors may lead to considerable progress in this regard. These inhibitors serve as a starting point for producing oral and effective components that could be used with statins to boost the proportion of patients who achieve their LDL-cholesterol goals. In this review, we have briefly summarised the recent information regarding natural components or extracts that have been shown to inhibit PCSK9 activity.

Exploring the Link between Plasma Levels of PCSK9, Immune Dysregulation and Atherosclerosis in Patients with Primary Sjögren's Syndrome.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates lipid metabolism contributing to cardiovascular (CV) risk in the general population. The relationship between PCSK9 and CV risk in systemic autoimmune diseases has been poorly explored. We investigated the association between plasma PCSK9, measures of immune-inflammatory status and markers of atherosclerosis in 52 consecutive patients with primary Sjögren's syndrome (pSS) in comparison to healthy controls (HCs). Median plasma PCSK9 levels were significantly higher in pSS patients versus HCs (162 (79-255) vs. 53 (39-99) ng/mL). Significantly higher prevalence of subclinical atherosclerosis and lower of dyslipidaemia (61% vs. 85%, p = 0.042) characterized pSS patients versus HCs. In pSS, no significant correlation emerged between PCSK9 and disease activity, atherosclerosis and lipid levels. In HCs, PCSK9 significantly correlated with lipid levels and atherosclerosis. Interestingly, significantly higher PCSK9 levels were found in HCs with high-to-very-high as compared to low-to-moderate CV risk (p = 0.018) while a non-significant trend towards higher PCSK9 levels was detected in pSS patients with low-to-moderate as compared to high-to-very-high CV risk (p = 0.060). This is the first demonstration that pSS patients, despite lower prevalence of dyslipidaemia and higher CV risk profile, are characterized by a 3-fold increase in PCSK9 levels in comparison to HCs. As PCSK9 does not correlate with measures of CV risk, its role in CV morbidity in pSS needs further investigation.

Circulating Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is Associated with Disease Activity and Risk of Incident Cardiovascular Disease in Patients with Systemic Lupus Erythematosus.

To study the relationship of serum PCSK9 and disease activity and major adverse cardiovascular events (MACEs) in systemic lupus erythematosus (SLE). Consecutive patients who fulfilled ≥ 4 ACR criteria for SLE and consented for a biomarker study in 2009-2013 were included. Stored serum samples were assayed for PCSK9. PCSK9 levels were correlated with SLE disease activity scores. Patients were divided into two groups according to the median PCSK9 level and new MACEs over time were evaluated. The effect of PCSK9 level on MACEs and mortality was studied by Cox regression, adjusted for confounders. A total of539 SLE patients were studied (93% women, age 41.9 ± 14.0 years). The median PCSK9 level at baseline was 220 ng/ml. Patients with higher PCSK9 (≥ 220 ng/ml; n = 269) had significantly higher SLE disease activity index (SLEDAI) than those with lower PCSK9 (< 220 ng/ml; n = 270). PCSK9 levels were significantly higher in patients with active renal than active non-renal SLE, which in turn were significantly higher than those with inactive SLE or healthy controls. PCSK9 level correlated with SLEDAI in the overall population (ρ = 0.30; p < 0.001). Over 91.3 ± 18.6 months, 29 patients developed 31 MACEs and 40 patients succumbed (25% for vascular events). The cumulative incidence of MACEs at 5 years was 4.8% in the higher PCSK9 and 1.1% in the lower PCSK9 group (HR2.51[1.11-5.70]; p = 0.03). Cox regression revealed higher PCSK9 was significantly associated with MACEs (HR1.003[1.000-1.005] per ng/ml; p = 0.02) independent of age, sex, renal function, baseline disease activity score, traditional atherosclerotic risk factors, antiphospholipid antibody and the use of aspirin/warfarin, statins and immunosuppressive drugs. PCSK9 level was also independently associated with all-cause (HR1.002[1.000-1.004] per ng/ml; p = 0.03) and vascular mortality (HR1.004[1.000-1.007]; p = 0.04). We concluded that serum PCSK9 level correlates with SLEdisease activity. Higher serum PCSK9 levels are associated with increased risk of cardiovascular events and mortality in SLE.

Proprotein convertase subtilisin/kexin type 9 inhibitors: prospects for cholesterol-lowering therapy in type 2 diabetes

Diabetic dyslipoproteinemia (DLP), characterized by quantitative, qualitative, and kinetic changes in all major circulating lipids, contributes to an increased risk of atherosclerotic cardiovascular disease in patients with type 2 diabetes mellitus (DM). Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) by human monoclonal antibodies is a promising treatment for diabetic DLP. Several drugs differ in their mechanisms of inhibition of PCSK9 activity. The following groups are conditionally distinguished: PCSK9 monoclonal antibodies (anti-PCSK9 monoclonal antibodies): evolocumab, alirocumab, bococizumab (injectable); other injectable medications with different mechanism of actions (inclisiran, SPC4061, SPC5001, adnectin BMS-962476, LIB003, anti-PCSK9 vaccine; anti-PCSK9 vaccine (nanoparticle-based); orally administered drugs (PF-06446846, DS-9001a, SRT3025); cholesteryl ester transfer protein/PCSK9 inhibitors (anacetrapib, evacetrapib, torcetrapib, K-312). This review aims to discuss the role of alirocumab and evolocumab, fully humanized monoclonal antibodies, in the treatment of type 2 DM patients with DLP and to consider their effectiveness and safety. Strategy of search. Scopus, Science Direct (from Elsevier), and PubMed, including the Medline databases, were searched. The following keywords were used: autonomic nervous system, heart rate variability, baroreflex sensitivity, diabetic cardiac autonomic neuropathy, and MeSH terms. A manual search of the bibliography of publications was used to identify research results that could not be found with the online search. Statins are the first line of choice for treating DLP in patients with type 2 DM to reduce the risk of atherosclerotic cardiovascular disease. Ezetimibe is the next drug to be added if patients’ low-density lipoprotein cholesterol levels are higher than acceptable. In cases of failure of the combination of statins with ezetimibe, PCSK9 inhibitor is a reasonable and rational choice. Overall, clinical data suggest that PCSK9 inhibitors are well tolerated and provide a significant reduction in low-density lipoprotein cholesterol levels in type 2 DM patients with DLP in addition to high-intensity statin therapy. The use of PCSK9 inhibitors is not associated with impaired glycemic control or increased risk of diabetes development in individuals without previously diagnosed DM and may prevent or reduce subsequent cardiovascular events.

Abstract 10451: Efficacy and Safety of Ebronucimab, a Monoclonal Antibody Against Pcsk9, in Patients With Hyperlipidemia: Result From a Phase 2, Randomized, Double-Blind, Placebo-Controlled Study

Introduction Elevated low-density lipoprotein cholesterol (LDL-C) is a well-recognized risk factor for cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to Low-density lipoprotein receptors (LDL-R) and triggers their degradation. Inhibiting PCSK9 activity results in lowering LDL-C levels and further reduceing the risk of cardiovascular events. Ebronucimab (AK102) is a novel fully human immunoglobulin G1 (IgG1) monoclonal antibody against PCSK9. Objectives To evaluate the safety, efficacy of ebronucimab and further identify the optimal dosing scheme in patients with hyperlipidemia. Methods A total of 260 Chinese patients with hyperlipidemia (≧18 years, male or female) were planned to be enrolled, and randomized to receive ebronucimab 450 mg every 4 weeks (q4w), 300 mg q4w, 150 mg q2w, 75 mg q2w or matching placebo via subcutaneous injection. The patients were treated up to 12 weeks (day 85). Serum samples were collected at preselected timepoints to analyze the lipid profiles. Results Efficacy Ebronucimab showed significant and dose-dependent LDL-C reductions from baseline. At week 12, the mean reductions in LDL-C were 65.48 %, 48.14%, 63.69% and 37.39% for 450 mg q4w, 300 mg q4w, 150 mg q2w and 75 mg q2w dose groups, respectively. Patients in the 450 mg q4w and 150 mg q2w groups achieved higher and more sustained LDL-C reduction compared with other dose groups. Similar trend was observed in serum levels of total cholesterol (TC), apolipoprotein B (ApoB), lipoprotien (a) (LP[a]). Safety A total of 49.6% (130/262) patients experienced at least 1 treatment-emergent adverse event (TEAE), 109 patients (109/210 [51.9%]) in ebronucimab groups and 21 patients (21/52 [40.4%]) in the placebo group. Most TEAEs were mild and moderate. No adverse events were apparently dose dependent with ebronucimab. The overall incidence of serious adverse events (SAEs) was 3.4 % (9/262). Conclusions Ebronucimab was generally safe and well tolerated in Chinese patients with hyperlipidemia. Patients treated with ebronucimab achieved a significant reduction in serum levels of LDL-C and other lipids, especially in 450 mg q4w and 150 mg q2w treatment groups.

Proprotein convertase subtilisin/kexin type 9 genetic screening using the vervet (Chlorocebus aethiops) model.

The proprotein convertase subtilisin/kexin type 9 (PCSK9) gene has come to prominence due to its reported function in the clearance of low-density lipoprotein cholesterol. The vervet monkey (Chlorocebus aethiops) was utilized to study the genetics of PCSK9 gene. Sixteen vervet monkeys were selected to screen for possible PCSK9 polymorphisms and to determine gene expression. Four PCSK9 sequence variants (T112T, R148S, H177N and G635G) were identified and three of these variants (H177N, R148S, and G635G) were categorized as loss of function mutations. A decline in gene expression levels was also observed in animals harboring these three variants. Although the selected variants might have affected the level of gene expression in the selected animals, individual variation was also noticed in some of these individuals with the G635G variant. Based on the findings obtained from this study, it is suggestive that the activity of PCSK9 was hindered.

PCSK9 association with LDL: Effects of anti-PCSK9 mAbs therapy

Background and Aims : Proprotein convertase subtilisin-kexin type 9 (PCSK9) increases LDL-C levels in plasma by promoting the degradation of the low-density lipoprotein receptor (LDLR). The use of monoclonal antibodies (mAbs) is an effective approach for the inhibition of PCSK9 activity. PCSK9 associates with LDL in plasma, and this is thought to have biological significance. The aim of our study was to clarify whether anti-PCSK9 mAbs can modify the PCSK9-LDL association.

Leu22_Leu23 Duplication at the Signal Peptide of PCSK9 Promotes Intracellular Degradation of LDLr and Autosomal Dominant Hypercholesterolemia.

PCSK9 (Proprotein convertase subtilisin/kexin type 9) regulates LDL-C (low-density lipoprotein cholesterol) metabolism by targeting LDLr (LDL receptor) for lysosomal degradation. PCSK9 gain-of-function variants cause autosomal dominant hypercholesterolemia by reducing LDLr levels, the D374Y variant being the most severe, while loss-of-function variants are associated with low LDL-C levels. Gain-of-function and loss-of-function activities have also been attributed to variants occurring in the PCSK9 signal peptide. Among them, L11 is a very rare PCSK9 variant that seems to increase LDL-C values in a moderate way causing mild hypercholesterolemia. Using molecular biology and biophysics methodologies, activities of L8 and L11 variants, both located in the leucine repetition stretch of the signal peptide, have been extensively characterized in vitro. L8 variant is not associated with increased LDLr activity, whereas L11 activity is increased by ≈20% compared with wt PCSK9. The results suggest that the L11 variant reduces LDLr levels intracellularly by a process resulting from impaired cleavage of the signal peptide. This would lead to less efficient LDLr transport to the cell membrane and promote LDLr intracellular degradation. Deletion of a leucine in the signal peptide in L8 variant does not affect PCSK9 activity, whereas the leucine duplication in the L11 variant enhances LDLr intracellular degradation. These findings highlight the importance of deep in vitro characterization of PCSK9 genetic variants to determine pathogenicity and improve clinical diagnosis and therapy of inherited familial hypercholesterolemia disease.

Proprotein convertase subtilisin/kexin type 9 is associated with atherosclerosis in patients with Behcet’s disease

ABSTRACT Objectives The incidence of cardiovascular disease is increased in patients with Behcet’s disease (BD). Proprotein convertase subtilisin/kexin type 9 (PCSK9) causes the acceleration of atherosclerosis. We aimed to investigate whether there is a relationship between PCSK9 with carotid artery intima-media thickness (cIMT), a marker of subclinical atherosclerosis, and BD disease activity. Methods Fifty-eight patients with BD and 58 age-, gender-, and body mass index (BMI)-matched healthy control subjects were included in the study. The disease activity of the patients was estimated. Individuals’ cIMT values were measured, and PCSK9 levels were studied. Results Patients with BD’ cIMT (0.51 ± 0.1 vs 0.41 ± 0.1 mm, p < .001) and PCSK9 (623.2 ± 101.7 ± 10.1 vs 528.3 ± 242.7 ng/ml, p = .007), values were significantly higher than the control group. In stepwise regression analysis, there was an independent relationship between cIMT with PCSK9 (β = 0.179, p < .050). There was no independent relationship between disease activities with PCSK9. Based on the ROC curve analysis, the PCSK9 optimal cutoff value for cIMT was 595.1 ng/ml, sensitivity 66.7%, specificity 64.7% (AUC = 0.672; 95% CI: 0.530–0.815, p = .040). Conclusion There is a strong independent association between subclinical atherosclerosis and PCSK9 in patients with BD. There may be no independent association between PCSK9 and disease activity.

The biological relevance of PCSK9: when less is better….

Proprotein Convertase Subtilisin/Kexin-type 9 (PCSK9) is a circulating negative regulator of hepatic low-density lipoprotein receptor (LDLR), which clears cholesterol from blood. Gain-of-function genetic mutations that amplify PCSK9 activity have been found to cause potentially lethal familial hypercholesterolemia. Inversely, reduction of its activity through loss-of-function genetics or with pharmaceuticals was shown to increase hepatic LDLR, to lower blood cholesterol, and to protect against cardiovascular diseases. New epidemiological and experimental evidence suggests that this reduction could also attenuate inflammation, reinforce cancer immunity, provide resistance to infections, and protect against liver pathologies. In this review, we question the relevance of this protein under normal physiology. We propose that PCSK9 is an important, but nonessential, modulator of cholesterol metabolism and immunity, and that its pathogenicity results from its chronic overexpression.

PCSK9 Inhibition-Based Therapeutic Approaches: An Immunotherapy Perspective.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (PCSK9-I) are novel therapeutic tools to decrease cardiovascular risk. These agents work by lowering the low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemic patients who are statin resistant/intolerant. Current clinically approved and investigational PCSK9- I act generally by blocking PCSK9 activity in the plasma or suppressing its expression or secretion by hepatocytes. The most widely investigated method is the disruption of PCSK9/LDL receptor (LDLR) interaction by fully-humanized monoclonal antibodies (mAbs), evolocumab and alirocumab, which have been approved for the therapy of hypercholesterolemia and atherosclerotic cardiovascular disease (CVD). Besides, a small interfering RNA called inclisiran, which specifically suppresses PCSK9 expression in hepatocytes, is as effective as mAbs but with administration twice a year. Because of the high costs of such therapeutic approaches, several other PCSK9-I have been surveyed, including peptide-based anti-PCSK9 vaccines and small oral anti-PCSK9 molecules, which are under investigation in preclinical and phase I clinical studies. Interestingly, anti-PCSK9 vaccination has been found to serve as a more widely feasible and more cost-effective therapeutic tool over mAb PCSK9-I for managing hypercholesterolemia. The present review will discuss LDL-lowering and cardioprotective effects of PCSK9-I, mainly immunotherapy- based inhibitors including mAbs and vaccines, in preclinical and clinical studies.

PCSK9 Activity Is Potentiated Through HDL Binding.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) circulates in a free and lipoprotein-bound form, yet the functional consequence of the association between PCSK9 and high-density lipoprotein (HDL) remains unexplored. This study sought to interrogate the novel relationship between PCSK9 and HDL in humans. Comparing lipoprotein and apolipoprotein profiles by nuclear magnetic resonance and targeted mass spectrometry measurements with PCSK9 levels in the community-based Bruneck (n=656) study revealed a positive association of plasma PCSK9 with small HDL, alongside a highly significant positive correlation between plasma levels of PCSK9 and apolipoprotein-C3, an inhibitor of lipoprotein lipase. The latter association was replicated in an independent cohort, the SAPHIR study (n=270). Thus, PCSK9-HDL association was determined during the postprandial response in two dietary studies (n=20 participants each, 8 times points). Peak triglyceride levels coincided with an attenuation of the PCSK9-HDL association, a loss of apolipoprotein-C3 from HDL and lower levels of small HDL as measured by nuclear magnetic resonance. Crosslinking mass spectrometry (XLMS) upon isolated HDL identified PCSK9 as a potential HDL-binding partner. PCSK9 association with HDL was confirmed through size-exclusion chromatography and immuno-isolation. Quantitative proteomics upon HDL isolated from patients with coronary artery disease (n=172) returned PCSK9 as a core member of the HDL proteome. Combined interrogation of the HDL proteome and lipidome revealed a distinct cluster of PCSK9, phospholipid transfer protein, clusterin and apolipoprotein-E within the HDL proteome, that was altered by sex and positively correlated with sphingomyelin content. Mechanistically, HDL facilitated PCSK9-mediated low-density lipoprotein receptor degradation and reduced low-density lipoprotein uptake through the modulation of PCSK9 internalisation and multimerisation. This study reports HDL as a binder of PCSK9 and regulator of its function. The combination of -omic technologies revealed postprandial lipaemia as a driver of PCSK9 and apolipoprotein-C3 release from HDL.

Naturalne inhibitory PCSK9 — przegląd substancji o możliwym wpływie na PCSK9

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein discovered in 2003 and playing an important role in lipoprotein metabolism. The main function of PCSK9 is to regulate the number of low-density lipoprotein (LDL) receptors on the surface of hepatocytes. The biological effect of PSCK9 is to reduce the number of LDL receptors on the surface of hepatocytes, which reduces their ability to take up LDL lipoproteins. PCSK9 inhibitors such as alirocumab, evolocumab or inclisiran are a new, very effective method of lipid-lowering therapy. Recently, a number of naturally derived compounds have been identified that are characterized by the ability to reduce the activity of PCSK9. These compounds are among the alkaloids, polyphenols, sterols, stanols, vegetable proteins and other nutrients and may find application in supporting the pharmacotherapy of lipid disorders.

Acaudina molpadioides mediates lipid uptake by suppressing PCSK9 transcription and increasing LDL receptor in human liver cells.

Acaudina molpadioides has been long used as traditional medicinal resources and reported to demonstrate various important bioactivities such as anticoagulation, antithrombosis, anti-hyperglycemia and anticancer. However, its lipid lowering activity is yet to be fully explored. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme that enhances the lysosomal degradation of hepatic low density lipoprotein receptor (LDLR) resulting in excessive accumulation of the plasma levels of LDL-cholesterols (LDL-C) which subsequently accelerate atherosclerosis. In the present study, A. molpadioides fractions were subjected to promoter-reporter luciferase assay to determine its role as PCSK9 inhibitors. It was found both fractions (EFA and EFB) reduced the transcriptional activity of PCSK9 promoter. Among the seven 5′end deletion constructs of PCSK9 promoter, fragments D1 (−1,711/−94), D3 (−709/−94) and D4 (−440/−94), were suppressed in the presence of both fractions whereas D2 (−1,214/−94), and, D6 (−351/−94) as well as D7 (−335/−94) were inhibited only by EFA and EFB, respectively. Further transcription factor binding sites prediction using MatInspector software discovered various potential cis-regulatory elements namely, PPAR, KLFs, RBPJ-kappa and SREBP that may potentially be involved in ameliorating the transcriptional activity of PCSK9. Immunofluorescence staining was used to evaluate the effects of both fractions on LDL-C and LDLR. Results showed that levels of LDL-C uptake in EFA-treated cells were 69.1% followed by EFB at 32.6%, as compared to untreated control after 24 h treatment. The LDLR protein distribution was induced by 62.41% and 32.2%, which corresponded to an increase in LDL-C uptake in both EFA and EFB treatment, respectively. Hence, the inhibition of PCSK9 by bioactive compounds in EFA and EFB could be another promising therapeutic agent in reducing the cholesterol levels and atherosclerosis by targeting PCSK9.

HDL compartmentalisation regulates PCSK9 activity

Background and Aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) circulates in a free and lipoprotein-bound form in plasma. This study sought to interrogate the novel relationship between PCSK9 and high-density lipoprotein (HDL).

Hypercholesterolemia in Progressive Renal Failure Is Associated with Changes in Hepatic Heparan Sulfate - PCSK9 Interaction.

Dyslipidemia is an important risk factor in CKD. The liver clears triglyceride-rich lipoproteins (TRL) via LDL receptor (LDLR), LDLR-related protein-1 (LRP-1), and heparan sulfate proteoglycans (HSPGs), mostly syndecan-1. HSPGs also facilitate LDLR degradation by proprotein convertase subtilisin/kexin type 9 (PCSK9). Progressive renal failure affects the structure and activity of hepatic lipoprotein receptors, PCSK9, and plasma cholesterol. Uninephrectomy- and aging-induced CKD in normotensive Wistar rats and hypertensive Munich-Wistar-Frömter (MWF) rats. Compared with 22-week-old sex- and strain-matched rats, 48-week-old uninephrectomized Wistar-CKD and MWF-CKD rats showed proteinuria, increased plasma creatinine, and hypercholesterolemia (all P<0.05), which were most apparent in hypertensive MWF-CKD rats. Hepatic PCSK9 expression increased in both CKD groups (P<0.05), with unusual sinusoidal localization, which was not seen in 22-week-old rats. Heparan sulfate (HS) disaccharide analysis, staining with anti-HS mAbs, and mRNA expression of HS polymerase exostosin-1 (Ext-1), revealed elongated HS chains in both CKD groups. Solid-phase competition assays showed that the PCSK9 interaction with heparin-albumin (HS-proteoglycan analogue) was critically dependent on polysaccharide chain length. VLDL binding to HS from CKD livers was reduced (P<0.05). Proteinuria and plasma creatinine strongly associated with plasma cholesterol, PCSK9, and HS changes. Progressive CKD induces hepatic HS elongation, leading to increased interaction with PCSK9. This might reduce hepatic lipoprotein uptake and thereby induce dyslipidemia in CKD. Therefore, PCSK9/HS may be a novel target to control dyslipidemia.

Hypolipidemic drugs inhibiting the proprotein convertase of subtilisin/kexin type 9 (PCSK9): monoclonal antibodies, antisense oligonucleotides, small interfering ribonucleic acids

Hypolipidemic therapy is one of the essential components for the management of patients with cardiovascular diseases (CVD). In this regard, the main task of modern research is to find new targets for creating additional effective groups of hypolipidemic drugs. In 2003, canadian and french research groups led by N. Seidah and M. Abifadel discovered a new enzyme proprotein convertase subtilisin/kexin type 9 (PCSK9), which later turned out to play an important role in lipid metabolism. The main mechanism of action of PCSK9 is to regulate the density of low-density lipoprotein receptors (LDLR) in the cell membrane of hepatocytes. Increased activity of PCSK9 significantly accelerates the degradation of LDL and leads to an increase in the concentration of atherogenic classes of lipoproteins-low-density lipoproteins (LDL). In contrast, reduced PCSK9 activity is accompanied by a decrease in LDL concentrations and a reduced risk of developing atherosclerosis and CVD. The second of the recently discovered and less studied mechanism of PCSK9 protearogenic action is an increase in inflammatory processes in the atherosclerotic plaque. Given this adverse contribution of PCSK9 to the development and progression of atherosclerosis and CVD, the main task of the researchers was to develop drugs that inhibit THIS enzyme. To date, several new groups of drugs have been developed that target the stages of biosynthesis and the function of PCSK9. In this article, we will focus in detail on discussing the mechanisms of action and effectiveness of the following groups of hypolipidemic drugs: anti-PCSK9 monoclonal antibodies (alirocumab, evolocumab), small interfering ribonucleic acids (incliciran), and antisense nucleotides.

New groups of hypolipidemic medications based on inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9). Part 1

Hypolipidemic therapy is one of the essential components for the management of patients with cardiovascular diseases (CVD). In this regard, the main task of modern research is to find new targets for creating additional effective groups of hypolipidemic medications. Canadian and French research groups led by N. Seidah and M. Abifadel discovered a new enzyme — proprotein convertase subtilisin-kexin type 9 (PCSK9) in 2003. It turned out to play an important role in lipid metabolism later. The main mechanism of action of PCSK9 is to regulate the density of low-density lipoprotein receptors (LDLR) in the cell membrane of hepatocytes. Increased activity of PCSK9 accelerates the degradation of LDL significantly, and leads to an increase in the concentration of atherogenic classes of lipoproteins — low-density lipoproteins (LDL). In contrast, reduced PCSK9 activity is accompanied by a decrease in LDL concentrations and a reduced risk of developing atherosclerosis and CVD. The second of the recently discovered and less studied mechanism of PCSK9 protearogenic action is an increase in inflammatory processes in the atherosclerotic plaque. Considering this adverse contribution of PCSK9 to the development and progression of atherosclerosis and CVD, the main task of the researchers was to develop medications that inhibit THIS enzyme. Several new groups of medications that target the stages of biosynthesis and the function of PCSK9 have been developed by now. In this article, we will focus on details discussing the mechanisms of action and effectiveness of the following groups of hypolipidemic medications: anti-PCSK9 monoclonal antibodies (alirocumab, evolocumab), small interfering ribonucleic acids (incliciran), and antisense nucleotides.

New groups of hypolipidemic drugs based on inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9). Part 1

The hypolipidemic therapy is one of the essential components for the management of patients with cardiovascular diseases (CVD). In this regard, the main task of modern research is to find new targets for creating additional effective groups of lipid-lowering drugs. In 2003, a Canadian and French research team led by N. Seidah and M. Abifadel discovered a new enzyme, proprotein convertase subtilisin-kexin type 9 (PCSK9), which plays an important role in lipid metabolism.&#x0D; The main mechanism of action of PCSK9 is to regulate the density of low-density lipoprotein receptors (LDLR) in the cell membrane of hepatocytes. The increased activity of PCSK9 significantly accelerates the degradation of LDLR and leads to an increase in the concentration of atherogenic classes of lipoproteins the low-density lipoproteins (LDL). A reduced activity of PCSK9, on the contrary, is accompanied by a decrease in the concentration of LDL and a decrease in the risk of developing atherosclerosis and CVD. The second, recently discovered and less studied, mechanism of the protearogenic action of PCSK9 is the enhancement of inflammatory processes in the atherosclerotic plaque. Given this unfavorable contribution of PCSK9 to the development and progression of atherosclerosis and CVD, the main task of the researchers was to develop drugs that inhibit this enzyme. To date, several new drug groups have been developed that target the biosynthesis steps and the function of PCSK9.&#x0D; In this article, we will focus in detail on the discussion of the mechanisms of action and effectiveness of the following groups of lipid-lowering drugs: anti-PCSK9 monoclonal antibodies (alirocumab, evolocumab), small interfering ribonucleic acids (incliciran) and antisense nucleotides.

A transient amphipathic helix in the prodomain of PCSK9 facilitates binding to low-density lipoprotein particles

Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a ligand of low-density lipoprotein (LDL) receptor (LDLR) that promotes LDLR degradation in late endosomes/lysosomes. In human plasma, 30–40% of PCSK9 is bound to LDL particles; however, the physiological significance of this interaction remains unknown. LDL binding in vitro requires a disordered N-terminal region in PCSK9's prodomain. Here, we report that peptides corresponding to a predicted amphipathic α-helix in the prodomain N terminus adopt helical structure in a membrane-mimetic environment. This effect was greatly enhanced by an R46L substitution representing an atheroprotective PCSK9 loss-of-function mutation. A helix-disrupting proline substitution within the putative α-helical motif in full-length PCSK9 lowered LDL binding affinity >5-fold. Modeling studies suggested that the transient α-helix aligns multiple polar residues to interact with positively charged residues in the C-terminal domain. Gain-of-function PCSK9 mutations associated with familial hypercholesterolemia (FH) and clustered at the predicted interdomain interface (R469W, R496W, and F515L) inhibited LDL binding, which was completely abolished in the case of the R496W variant. These findings shed light on allosteric conformational changes in PCSK9 required for high-affinity binding to LDL particles. Moreover, the initial identification of FH-associated mutations that diminish PCSK9's ability to bind LDL reported here supports the notion that PCSK9-LDL association in the circulation inhibits PCSK9 activity.