Angewandte Chemie - International Edition p. 16218 - 16222 (2017)
Update date:2022-08-30
Topics:
McClure, Kim F.
Piotrowski, David W.
Petersen, Donna
Wei, Liuqing
Xiao, Jun
Londregan, Allyn T.
Kamlet, Adam S.
Dechert-Schmitt, Anne-Marie
Raymer, Brian
Ruggeri, Roger B.
Canterbury, Daniel
Limberakis, Chris
Liras, Spiros
DaSilva-Jardine, Paul
Dullea, Robert G.
Loria, Paula M.
Reidich, Benjamin
Salatto, Christopher T.
Eng, Heather
Kimoto, Emi
Atkinson, Karen
King-Ahmad, Amanda
Scott, Dennis
Beaumont, Kevin
Chabot, Jeffrey R.
Bolt, Michael W.
Maresca, Kevin
Dahl, Kenneth
Arakawa, Ryosuke
Takano, Akihiro
Halldin, Christer
Targeting of the human ribosome is an unprecedented therapeutic modality with a genome-wide selectivity challenge. A liver-targeted drug candidate is described 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 by 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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