2. Academic Validation
  3. Efficient Liver Targeting by Polyvalent Display of a Compact Ligand for the Asialoglycoprotein Receptor

Efficient Liver Targeting by Polyvalent Display of a Compact Ligand for the Asialoglycoprotein Receptor

  • J Am Chem Soc. 2017 Mar 8;139(9):3528-3536. doi: 10.1021/jacs.6b12964.
Carlos A Sanhueza 1 2,  Michael M Baksh 1 2,  Benjamin Thuma 3,  Marc D Roy 4,  Sanjay Dutta 2,  Cathy Préville 3,  Boris A Chrunyk 3,  Kevin Beaumont 5,  Robert Dullea 6,  Mark Ammirati 3,  Shenping Liu 3,  David Gebhard 3,  James E Finley 4,  Christopher T Salatto 6,  Amanda King-Ahmad 3,  Ingrid Stock 3,  Karen Atkinson 3,  Benjamin Reidich 6,  Wen Lin 3,  Rajesh Kumar 7,  Meihua Tu 5,  Elnaz Menhaji-Klotz 5,  David A Price 5,  Spiros Liras 5,  M G Finn 1 2,  Vincent Mascitti 3
Affiliations

Affiliations

  • 1 School of Chemistry & Biochemistry, Georgia Institute of Technology , 901 Atlantic Avenue, Atlanta, Georgia 30332, United States.
  • 2 Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute , 10550 N. Torrey Pines Road, La Jolla, California 92037, United States.
  • 3 Pfizer Medicine Design , Eastern Point Road, Groton, Connecticut 06340, United States.
  • 4 Pfizer Drug Safety R&D , Eastern Point Road, Groton, Connecticut 06340, United States.
  • 5 Pfizer Medicine Design , Main Street, Cambridge, Massachusetts 02139, United States.
  • 6 Pfizer CVMET Biology , Main Street, Cambridge, Massachusetts 02139, United States.
  • 7 Pfizer Medicinal Sciences , Eastern Point Road, Groton, Connecticut 06340, United States.
PMID: 28230359 DOI: 10.1021/jacs.6b12964
Abstract

A compact and stable bicyclic bridged ketal was developed as a ligand for the asialoglycoprotein receptor (ASGPR). This compound showed excellent ligand efficiency, and the molecular details of binding were revealed by the first X-ray crystal structures of ligand-bound ASGPR. This analogue was used to make potent di- and trivalent binders of ASGPR. Extensive characterization of the function of these compounds showed rapid ASGPR-dependent cellular uptake in vitro and high levels of liver/plasma selectivity in vivo. Assessment of the biodistribution in rodents of a prototypical Alexa647-labeled trivalent conjugate showed selective hepatocyte targeting with no detectable distribution in nonparenchymal cells. This molecule also exhibited increased ASGPR-directed hepatocellular uptake and prolonged retention compared to a similar GalNAc derived trimer conjugate. Selective release in the liver of a passively permeable small-molecule cargo was achieved by retro-Diels-Alder cleavage of an oxanorbornadiene linkage, presumably upon encountering intracellular thiol. Therefore, the multicomponent construct described here represents a highly efficient delivery vehicle to hepatocytes.

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