Inhibition of low-density lipoprotein receptor degradation with a cyclic peptide that disrupts the homodimerization of IDOL E3 ubiquitin ligase

Leitch, Eilidh K.; Elumalai, Nagarajan; Fridén-Saxin, Maria; Dahl, Göran; Wan, Paul; Clarkson, Paul; Valeur, Eric; Pairaudeau, Garry; Boyd, Helen; Tavassoli, Ali

doi:10.1039/c8sc01186a

Cited by 19 publications

(22 citation statements)

References 40 publications

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“…Although effective IDOL-targeted therapies have yet to be developed, several recent studies have demonstrated that natural compounds including docosahexanoic acid and xantholhumol modulate hepatic LDLR abundance via suppression of IDOL expression 16 , 17 . In addition, a recent study identified a cyclic peptide that disrupts IDOL homodimerization as an IDOL inhibitor and showed that it increased LDLR levels in HepG2 cells 18 .…”

Section: Introductionmentioning

confidence: 99%

Platycodin D enhances LDLR expression and LDL uptake via down-regulation of IDOL mRNA in hepatic cells

Choi

Lee

Kim

et al. 2020

Sci Rep

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The root of Platycodon grandiflorum (PG) has long been used as a traditional herbal medicine in Asian country. Platycondin D (PD), triterpenoid saponin that is a main constituent of PG, exhibits various biological activities such as anti-inflammatory, anti-oxidant, anti-diabetic, and anti-cancer effects. A previous study showed that PD had cholesterol-lowering effects in mice that develop hypercholesterolemia, but the underlying molecular mechanisms have not been elucidated during the last decade. Here, we demonstrated that both PG and PD markedly increased levels of cell surface low-density lipoprotein receptor (LDLR) by down-regulation of the E3 ubiquitin ligase named inducible degrader of the LDLR (IDOL) mRNA, leading to the enhanced uptake of LDL-derived cholesterol (LDL-C) in hepatic cells. Furthermore, cycloheximide chase analysis and in vivo ubiquitination assay revealed that PD increased the half-life of LDLR protein by reducing IDOL-mediated LDLR ubiquitination. Finally, we demonstrated that treatment of HepG2 cells with simvastatin in combination with PG and PD had synergistic effects on the improvement of LDLR expression and LDL-C uptake. Together, these results provide the first molecular evidence for anti-hypercholesterolemic activity of PD and suggest that PD alone or together with statin could be a potential therapeutic option in the treatment of atherosclerotic cardiovascular disease.

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Section: Introductionmentioning

confidence: 99%

Platycodin D enhances LDLR expression and LDL uptake via down-regulation of IDOL mRNA in hepatic cells

Choi

Lee

Kim

et al. 2020

Sci Rep

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“…Similar to other ubiquitinated proteins, the ubiquitinated LDLR is easy to degrade. Unlike other ubiquitinated proteins, which degraded in proteasome where IDOL also catalyzes its own degradation, LDLR is usually degraded in lysosomes 24 , 25 .…”

Section: Discussionmentioning

confidence: 99%

IDOL gene variant is associated with hyperlipidemia in Han population in Xinjiang, China

Adi

Abuzhalihan

Wang

et al. 2020

Sci Rep

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Hyperlipidemia is one of the main risk factors that contributed to atherosclerosis and coronary artery disease (cAD). in the present study, our objective was to explore whether some genetic variants of human iDoL gene were associated with hyperlipidemia among Han population in Xinjiang, china. We designed a case-control study. A total of 1,172 subjects (588 diagnosed hyperlipidemia cases and 584 healthy controls) of Chinese Han were recruited. We genotyped three SNPs (rs9370867, rs909562, and rs2072783) of IDOL gene in all subjects by using the improved multiplex ligation detection reaction (iMLDR) method. our study demonstrated that the distribution of the genotypes, the dominant model (AA vs GG + GA), and the overdominant model (AA + GG vs GA) of the rs9370867 SNP had significant differences between the case group and controls (all P < 0.001). For rs909562 and rs2072783, the distribution of the genotypes, the recessive model (AA + GA vs GG) showed significant differences between the case subjects and controls (P = 0.002, P = 0.007 and P = 0.045, P = 0.02, respectively). After multivariate adjustment for several confounders, the rs9370867 SNP is still an independent risk factor for hyperlipidemia [odds ratio (OR) = 1.380, 95% confidence interval (CI) = 1.201-1.586, P < 0.001]. The rs9370867 of human IDOL gene was associated with hyperlipidemia in Han population. Abbreviations CAD Coronary artery disease HDL High-density lipoprotein LDL Low-density lipoprotein TC Total cholesterol TG Triglyceride SBP Systolic blood pressure DBP Diastolic blood pressure BUN Blood urea nitrogen Cr Creatinine FPG Fasting plasma glucose Hyperlipidemia is defined as increased levels of plasma total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), or triglyceride (TG) and along with or without decreased level of high-density lipoprotein cholesterol (HDL-C) 1. Hyperlipidemia is one of the main risk factors that contributed to atherosclerosis and coronary artery disease (CAD) 2,3. Previous studies on molecular mechanisms of hyperlipidemia revealed that multiple risk factors,

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“…2019). The system can also be utilized to discover inhibitors of protein dimerization like the cyclic peptide inhibitors found to prevent the homodimerization of IDOL E3 ubiquitin ligase with a K D of 4.6 µM (Leitch et al, 2018) and BCL6 with a K D of 142 µM (Osher et al, 2018). In addition, even correctors of protein misfolding can be identified using SICLOPPS-based screening (Matis et al, 2017).…”

Section: Protein Splicing Methodsmentioning

confidence: 99%

Methodologies for Backbone Macrocyclic Peptide Synthesis Compatible With Screening Technologies

et al. 2020

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Backbone macrocyclic structures are often found in diverse bioactive peptides and contribute to greater conformational rigidity, peptidase resistance, and potential membrane permeability compared to their linear counterparts. Therefore, such peptide scaffolds are an attractive platform for drug-discovery endeavors. Recent advances in synthetic methods for backbone macrocyclic peptides have enabled the discovery of novel peptide drug candidates against diverse targets. Here, we overview recent technical advancements in the synthetic methods including 1) enzymatic synthesis, 2) chemical synthesis, 3) split-intein circular ligation of peptides and proteins (SICLOPPS), and 4) in vitro translation system combined with genetic code reprogramming. We also discuss screening methodologies compatible with those synthetic methodologies, such as one-beads one-compound (OBOC) screening compatible with the synthetic method 2, cell-based assay compatible with 3, limiting-dilution PCR and mRNA display compatible with 4.

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Inhibition of low-density lipoprotein receptor degradation with a cyclic peptide that disrupts the homodimerization of IDOL E3 ubiquitin ligase

Abstract: A cyclic peptide IDOL homodimerization inhibitor identified from a genetically encoded SICLOPPS library is active in vitro and in cells.

Cited by 19 publications

References 40 publications

Platycodin D enhances LDLR expression and LDL uptake via down-regulation of IDOL mRNA in hepatic cells

Platycodin D enhances LDLR expression and LDL uptake via down-regulation of IDOL mRNA in hepatic cells

IDOL gene variant is associated with hyperlipidemia in Han population in Xinjiang, China

Methodologies for Backbone Macrocyclic Peptide Synthesis Compatible With Screening Technologies

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