LDL-R promoting activity of peptides derived from human PCSK9 catalytic domain (153–421): Design, synthesis and biochemical evaluation

Alghamdi, Rasha H.; O’Reilly, Paul G.; Lu, Chunyu; Gomes, James; Lagace, Thomas A.; Basak, Ajoy

doi:10.1016/j.ejmech.2015.01.022

Cited by 37 publications

(32 citation statements)

References 77 publications

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“…Mimetic peptides that inhibit the interaction between PCSK9 and the LDLR include several short amino acid sequences that mimic the EGF-A [35,57,58] , catalytic domain, prodomain, or C-terminal domain of PCSK9 [25,59,60] . These therapeutic small peptides have high specificity, are easy to produce and modify, and are cheaper to produce than antibodies, but their routes of administration are limited.…”

Section: Mimetic Peptidesmentioning

confidence: 99%

Lowering serum lipids via PCSK9-targeting drugs: current advances and future perspectives

et al. 2017

Acta Pharmacol Sin

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Proprotein convertase subtilisin/kexin type 9 (PCSK9), also known as neural apoptosis regulated convertase (NARC1), is a key modulator of cholesterol metabolism. PCSK9 increases the serum concentration of low-density lipoprotein cholesterol by escorting low-density lipoprotein receptors (LDLRs) from the membrane of hepatic cells into lysosomes, where the LDLRs are degraded. Owing to the importance of PCSK9 in lipid metabolism, considerable effort has been made over the past decade in developing drugs targeting PCSK9 to lower serum lipid levels. Nevertheless, some problems and challenges remain. In this review we first describes the structure and function of PCSK9 and its gene polymorphisms. We then discuss the various designs of pharmacological targets of PCSK9, including those that block the binding of PCSK9 to hepatic LDLRs (mimetic peptides, adnectins, and monoclonal antibodies), inhibit PCSK9 expression (the clustered regularly interspaced short palindromic repeats/Cas9 platform, small molecules, antisense oligonucleotides, and small interfering RNAs), and interfere with PCSK9 secretion. Finally, this review highlights future challenges in this field, including safety concerns associated with PCSK9 monoclonal antibodies, the limited utility of PCSK9 inhibitors in the central nervous system, and the cost-effectiveness of PCSK9 inhibitors.

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Section: Mimetic Peptidesmentioning

confidence: 99%

Lowering serum lipids via PCSK9-targeting drugs: current advances and future perspectives

et al. 2017

Acta Pharmacol Sin

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“…This approach has been used to modify the ability of PCSK9 to interact with LDL-Rs. As described above, the catalytic domain of PCSK9 binds to the EGF-A of LDL-R, 14,125 directing the complex toward lysosomal degradation rather than recycling of LDL-R. Several small peptides inhibiting this interaction have been developed, including mimetic peptides to EGF-A, 14,61,126 the catalytic domain of PCSK9, 127 the prodomain of PCSK9, 128 and the C-terminal domain of PCSK9. 129 As therapeutic tools, small peptides are highly selective, relatively easy to synthesize and modify, and less costly to produce than antibodies.…”

Section: Mimetic Peptidesmentioning

confidence: 99%

“…Small peptides engineered to mimic the EGF-A domain have been reported to bind to the catalytic domain of PCSK9 and, through competitive inhibition, to limit the interaction between PCSK9 and LDL-R. 14,127 Thus, a synthetic EGF-A mimetic peptide was shown to inhibit PCSK9-induced degradation of LDL-R in HepG2 cells in a dose-dependent manner. 61 Another synthetic peptide mimicking the H306Y gain-of-function mutation in the EGF-A domain was shown to inhibit binding of PCSK9 to LDL-R and to successfully recover LDL-R expression in vitro.…”

Section: Mimetic Peptides To Egf-amentioning

confidence: 99%

“…Mimetic peptides targeting gain-of-function mutations in the catalytic domain of PCSK9 have recently been tested and found to restore LDL-R recycling in vitro. 127 Three mimetic peptides derived from the prosegment of PCSK9 were shown to increase LDL-R levels in vitro, 128 but their effects on LDL in vivo have not been investigated. Small mimetic peptides to annexin-A2, an endogenous natural antagonist that binds to the C-terminal domain of PCSK9, have also been proposed as a potential approach for PCSK9 inhibition.…”

Section: Mimetic Peptides To Egf-amentioning

confidence: 99%

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Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition

Bergeron¹,

et al. 2015

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Abstract-Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in the regulation of cholesterol homeostasis. By binding to hepatic low-density lipoprotein (LDL) receptors and promoting their lysosomal degradation, PCSK9 reduces LDL uptake, leading to an increase in LDL cholesterol concentrations. Gain-of-function mutations in PCSK9 associated with high LDL cholesterol and premature cardiovascular disease have been causally implicated in the pathophysiology of autosomal-dominant familial hypercholesterolemia. In contrast, the more commonly expressed loss-of-function mutations in PCSK9 are associated with reduced LDL cholesterol and cardiovascular disease risk. The development of therapeutic approaches that inhibit PCSK9 function has therefore attracted considerable attention from clinicians and the pharmaceutical industry for the management of hypercholesterolemia and its associated cardiovascular disease risk. This review summarizes the effects of PCSK9 on hepatic and intestinal lipid metabolism and the more recently explored functions of PCSK9 in extrahepatic tissues. Therapeutic approaches that prevent interaction of PCSK9 with hepatic LDL receptors (monoclonal antibodies, mimetic peptides), inhibit PCSK9 synthesis in the endoplasmic reticulum (antisense oligonucleotides, siRNAs), and interfere with PCSK9 function (small molecules) are also described. Finally, clinical trials testing the safety and efficacy of monoclonal antibodies to PCSK9 are reviewed. These have shown dose-dependent decreases in LDL cholesterol (44%-65%), apolipoprotein B (48%-59%), and lipoprotein(a) (27%-50%) without major adverse effects in various high-risk patient categories, including those with statin intolerance. Initial reports from 2 of these trials have indicated the expected reduction in cardiovascular events. Hence, inhibition of PCSK9 holds considerable promise as a therapeutic option for decreasing cardiovascular disease risk.

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“…Ein Ziel ist hier die Bindungsstelle des PCSK9-Moleküls für die EGF-A-Domäne des LDL-Rezeptors [5,48,49]. Hierdurch kann experimentell der PCSK-9-vermittelte LDL-RezeptorAbbau verhindert werden.…”

Section: Weitere Pharmakologische Optionen Zur Pcsk9-reduktionunclassified

PCSK9 − „missing link“ der familiären Hypercholesterinämie

Thiery

Burkhardt

2016

Herz

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LDL-R promoting activity of peptides derived from human PCSK9 catalytic domain (153–421): Design, synthesis and biochemical evaluation

Cited by 37 publications

References 77 publications

Lowering serum lipids via PCSK9-targeting drugs: current advances and future perspectives

Lowering serum lipids via PCSK9-targeting drugs: current advances and future perspectives

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition

PCSK9 − „missing link“ der familiären Hypercholesterinämie

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