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

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


Targeting of the human ribosome is an unprecedented therapeutic modality with a genome-wide selectivity challenge. Herein we describe a liver-targeted drug candidate that inhibits ribosomal synthesis of PCSK9, a lipid regulator considered undruggable by small molecules. Key to the concept was the identification of pharmacologically active zwitterions designed to be retained in the liver. Oral delivery of the poorly permeable zwitterions was achieved via prodrugs susceptible to cleavage by carboxylesterase 1. The synthesis of select tetrazole prodrugs was crucial. A cell free in vitro translation assay containing human cell lysate and purified target mRNA fused to a reporter was used to identify active zwitterions. In vivo PCSK9 lowering by oral dosing of the candidate prodrug and quantification of the drug fraction delivered to the liver utilizing an oral positron emission tomography 18F-isotopologue validated our liver-targeting approach

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