A novel small-molecule PCSK9 inhibitor E28362 ameliorates hyperlipidemia and atherosclerosis.

Area of Science:

• Pharmacology
• Biochemistry
• Cardiovascular Research

Background:

• Proprotein convertase subtilisin/kexin type 9 (PCSK9) elevates plasma LDL-C by promoting lysosomal degradation of the LDL receptor (LDLR).
• PCSK9 inhibition is a key strategy for managing hypercholesterolemia and atherosclerosis.
• Targeting PCSK9 offers a novel therapeutic approach for cholesterol management.

Purpose of the Study:

• To identify and characterize a novel small-molecule PCSK9 inhibitor.
• To evaluate the efficacy of the identified inhibitor, E28362, in preclinical models of hyperlipidemia and atherosclerosis.
• To elucidate the mechanism of action of E28362 in regulating LDLR and PCSK9 levels.

Main Methods:

• Virtual screening of 40,000 compounds to identify PCSK9 inhibitors.
• In vitro studies using HepG2, AML12, and HEK293a cells to assess LDLR levels, LDL uptake, and cytotoxicity.
• In vivo studies in golden hamsters, ApoE-/- mice, and PCSK9 D374Y overexpression mice to evaluate effects on lipid profiles and atherosclerotic lesions.

Main Results:

• E28362 dose-dependently increased LDLR protein levels and enhanced LDL uptake in cell lines with no observed toxicity.
• E28362 significantly reduced plasma total cholesterol, triglyceride, LDL-C, and PCSK9 levels in hyperlipidemic hamsters.
• E28362 decreased plasma LDL-C and atherosclerotic lesion areas in ApoE-/- and PCSK9 D374Y mice, while increasing hepatic LDLR expression.
• E28362 was found to selectively bind PCSK9, block LDLR interaction, and promote PCSK9 degradation via the ubiquitin-proteasome pathway.

Conclusions:

• E28362 effectively inhibits PCSK9, increases LDLR levels, and ameliorates hyperlipidemia and atherosclerosis in multiple animal models.
• E28362 acts by blocking PCSK9-LDLR interaction and inducing PCSK9 degradation.
• E28362 represents a promising small-molecule therapeutic candidate for hypercholesterolemia and atherosclerosis.