ArticleThe Journal of biological chemistry2014
Identification of a small peptide that inhibits PCSK9 protein binding to the low density lipoprotein receptor.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
What it found
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Who cites it
59 citing papers in PubMed, 151 citations in OpenAlex.
- A phase 1 study to evaluate the safety and LDL cholesterol-lowering effects of RG7652, a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9.Clinical cardiology · 2017Trial
- Identification of a peptide inhibitor disrupting the PCSK9-LDLR interactionJournal of enzyme inhibition and medicinal chemistry · 2026Article
- PCSK9 as a Potential Regulator of Endothelial Dysfunction: Mechanistic Insights and Future Directions.International journal of molecular sciences · 2026Review
- Enzyme-Assisted Synthesis and In Vitro Characterization of Bifunctional PCSK9 Inhibitors.Chembiochem : a European journal of chemical biology · 2026Article
- A Pre-Clinical Study on the Use of the Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor PEP 2-8 to Mitigate Ischemic Injury in a Rat Marginal Donor Model.International journal of molecular sciences · 2025Article
- Rapid prediction of key residues for foldability by machine learning model enables the design of highly functional libraries with hyperstable constrained peptide scaffolds.PLoS computational biology · 2024Article
- Ferritin-based disruptor nanoparticles: A novel strategy to enhance LDL cholesterol clearance via multivalent inhibition of PCSK9-LDL receptor interaction.Protein science : a publication of the Protein Society · 2024Article
- Therapeutic peptides for coronary artery diseases: in silico methods and current perspectives.Amino acids · 2024Review
- Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside.Signal transduction and targeted therapy · 2024Review
- The Link between miRNAs and PCKS9 in Atherosclerosis.Current medicinal chemistry · 2024Review
- PCSK9-antibodies fail to block PCSK9-induced inflammation in macrophages and cannot recapitulate protective effects of PCSK9-deficiency in experimental myocardial infarction.Frontiers in cardiovascular medicine · 2024Article
- Disulfide-constrained peptide scaffolds enable a robust peptide-therapeutic discovery platform.PloS one · 2024Article
- Computational Design, Synthesis, and Biological Evaluation of Diimidazole Analogues Endowed with Dual PCSK9/HMG-CoAR-Inhibiting Activity.Journal of medicinal chemistry · 2023Article
- The evolving landscape of PCSK9 inhibition in cancer.European journal of pharmacology · 2023Review
- Article
- Brazilin fromAdvances in pharmacological and pharmaceutical sciences · 2023Article
- Review
- Review
- Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Deletion but Not Inhibition of Extracellular PCSK9 Reduces Infarct Sizes Ex Vivo but Not In Vivo.International journal of molecular sciences · 2022Article
- Charge-Sensitive Optical Detection of Binding Kinetics between Phage-Displayed Peptide Ligands and Protein Targets.Biosensors · 2022Article
Corrections and comments
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
Abstract
PCSK9 (proprotein convertase subtilisin/kexin type 9) is a negative regulator of the hepatic LDL receptor, and clinical studies with PCSK9-inhibiting antibodies have demonstrated strong LDL-c-lowering effects. Here we screened phage-displayed peptide libraries and identified the 13-amino acid linear peptide Pep2-8 as the smallest PCSK9 inhibitor with a clearly defined mechanism of inhibition that has been described. Pep2-8 bound to PCSK9 with a KD of 0.7 μm but did not bind to other proprotein convertases. It fully restored LDL receptor surface levels and LDL particle uptake in PCSK9-treated HepG2 cells. The crystal structure of Pep2-8 bound to C-terminally truncated PCSK9 at 1.85 Å resolution showed that the peptide adopted a strand-turn-helix conformation, which is remarkably similar to its solution structure determined by NMR. Consistent with the functional binding site identified by an Ala scan of PCSK9, the structural Pep2-8 contact region of about 400 Å(2) largely overlapped with that contacted by the EGF(A) domain of the LDL receptor, suggesting a competitive inhibition mechanism. Consistent with this, Pep2-8 inhibited LDL receptor and EGF(A) domain binding to PCSK9 with IC50 values of 0.8 and 0.4 μm, respectively. Remarkably, Pep2-8 mimicked secondary structural elements of the EGF(A) domain that interact with PCSK9, notably the β-strand and a discontinuous short α-helix, and it engaged in the same β-sheet hydrogen bonds as EGF(A) does. Although Pep2-8 itself may not be amenable to therapeutic applications, this study demonstrates the feasibility of developing peptidic inhibitors to functionally relevant sites on PCSK9.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.