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
  • 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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