Liver-Targeted Small-Molecule Inhibitors of Proprotein Convertase Subtilisin/Kexin Type 9 Synthesis.

Area of Science:

• Pharmacology
• Drug Discovery
• Molecular Biology

Background:

• Targeting the human ribosome presents a significant therapeutic challenge due to genome-wide selectivity issues.
• Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of lipid metabolism and is considered undruggable by traditional small molecules.
• Developing liver-specific therapeutics is crucial for managing metabolic diseases.

Purpose of the Study:

• To develop a liver-targeted therapeutic strategy for inhibiting PCSK9 synthesis.
• To identify and synthesize novel pharmacologically active zwitterions with liver retention properties.
• To enable oral delivery of poorly permeable zwitterions via a prodrug approach.

Main Methods:

• Identification of active zwitterions using a cell-free in vitro translation assay with human cell lysate and reporter-fused target mRNA.
• Synthesis of tetrazole prodrugs to facilitate oral delivery of zwitterions via carboxylesterase 1 (CES1) cleavage.
• In vivo validation using oral positron emission tomography (PET) with an 18F-isotopologue to quantify liver drug delivery and PCSK9 lowering.

Main Results:

• Successfully identified pharmacologically active zwitterions with potential for liver retention.
• Developed orally bioavailable prodrugs enabling delivery of zwitterions via CES1 cleavage.
• Demonstrated in vivo PCSK9 lowering and confirmed liver targeting using PET imaging.

Conclusions:

• The developed liver-targeted drug candidate represents an unprecedented therapeutic modality for inhibiting PCSK9.
• The prodrug strategy effectively overcomes oral delivery challenges associated with zwitterionic compounds.
• This approach validates a novel method for achieving liver selectivity and therapeutic efficacy against a previously undruggable target.