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Related Concept Videos

Lipid-Lowering Drugs: Statins and Miscellaneous Agents01:20

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Hyperlipidemia, a medical condition often referred to as high cholesterol, is characterized by abnormally elevated levels of lipids in the bloodstream. When present in excess, these lipids, specifically cholesterol and triglycerides, can lead to serious health complications, often involving cardiovascular diseases. Illnesses like atherosclerosis, heart attacks, and pancreatitis have all been linked to untreated hyperlipidemia. This means controlling and regulating cholesterol and triglyceride...
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Updated: Oct 28, 2025

A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
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Potent Lys Patch-Containing Stapled Peptides Targeting PCSK9.

Kévin Bourbiaux1,2, Baptiste Legrand1, Pascal Verdié1

  • 1IBMM, ENSCM, Université de Montpellier, CNRS, 34093 Montpellier, France.

Journal of Medicinal Chemistry
|July 16, 2021
PubMed
Summary
This summary is machine-generated.

Researchers modified a peptide inhibitor (Pep2-8) to create potent compounds that block the PCSK9/LDLR interaction, offering new strategies for cardiovascular disease treatment.

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Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Cardiovascular Research

Background:

  • Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low-density lipoprotein receptor (LDLR) and is implicated in cardiovascular diseases (CVD).
  • A previously identified peptide, Pep2-8, inhibits the PCSK9/LDLR interaction.

Purpose of the Study:

  • To modify the Pep2-8 peptide using stapled peptide and SIP technologies.
  • To develop novel PCSK9 inhibitors with improved potency and efficacy.

Main Methods:

  • Peptide modification using stapled peptide and SIP technologies.
  • Biochemical assays to measure PCSK9/LDLR binding inhibition (KD).
  • Cell-based assays (HepG2 cells) to assess LDL uptake restoration (EC50).
  • Structural studies using circular dichroism, nuclear magnetic resonance, and molecular dynamics simulations.

Main Results:

  • Developed potent modified peptides, including compound 18, which inhibited PCSK9/LDLR binding with a KD of 6 ± 1 nM.
  • Restored in vitro LDL uptake in HepG2 cells in the presence of PCSK9 with an EC50 of 175 ± 40 nM.
  • Elucidated 3D structures and binding modes to rationalize structure-activity relationships (SAR).

Conclusions:

  • The combination of stapled peptide and SIP technologies yields highly potent PCSK9 inhibitors.
  • These novel compounds demonstrate potential for therapeutic intervention in cardiovascular diseases by modulating PCSK9/LDLR interaction.