Identification of a PCSK9-LDLR disruptor peptide with in vivo function

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Proprotein convertase subtilisin/kexin type 9 (PCSK9) elevates LDL-C by degrading hepatic LDL receptors (LDLR).
• Current antibody therapies targeting PCSK9-LDLR binding reduce cardiovascular disease risk.
• The flat interface between PCSK9 and LDLR's EGF-A domain poses challenges for small molecule inhibitor development.

Purpose of the Study:

• To identify novel small molecules that disrupt the PCSK9-LDLR interaction.
• To develop a small molecule PCSK9-LDLR disruptor with therapeutic potential.
• To characterize the mechanism of action and in vivo efficacy of identified compounds.

Main Methods:

• Affinity-based screening of 10^13 in vitro-translated macrocyclic peptides.
• Structure-based design for optimizing small molecule function and pharmacokinetics.
• In vivo studies in mice to assess plasma cholesterol reduction and hepatic LDLR density.

Main Results:

• Identification of high-affinity PCSK9 ligands using an induced-fit pocket.
• Development of a small molecule (13PCSK9i) with enhanced function and pharmacokinetics.
• Demonstration of dose-dependent reduction in plasma cholesterol and increased hepatic LDLR density in mice.
• Characterization of 13PCSK9i's unique, allosteric mechanism of action.

Conclusions:

• 13PCSK9i is the smallest molecule identified to date with in vivo PCSK9-LDLR disruptor function.
• This allosteric inhibitor represents a novel therapeutic approach for lowering LDL-C.
• The findings open new avenues for developing small molecule therapies targeting PCSK9.