title: Efficient Liver Targeting by Polyvalent Display of a Compact Ligand for the Asialoglycoprotein Receptor.
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.
authors.affiliation: School of Chemistry & Biochemistry, Georgia Institute of Technology , 901 Atlantic Avenue, Atlanta, Georgia 30332, United States.|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.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Sanhueza
authors.affiliation: School of Chemistry & Biochemistry, Georgia Institute of Technology , 901 Atlantic Avenue, Atlanta, Georgia 30332, United States.|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.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Baksh
authors.affiliation: Pfizer Medicine Design , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Thuma
authors.affiliation: Pfizer Drug Safety R&D , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Marc D
authors.initials: MD
authors.lastname: Roy
authors.affiliation: 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.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Dutta
authors.affiliation: Pfizer Medicine Design , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Cathy
authors.initials: C
authors.lastname: Préville
authors.affiliation: Pfizer Medicine Design , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Boris A
authors.initials: BA
authors.lastname: Chrunyk
authors.affiliation: Pfizer Medicine Design , Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Beaumont
authors.affiliation: Pfizer CVMET Biology , Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Dullea
authors.affiliation: Pfizer Medicine Design , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Ammirati
authors.affiliation: Pfizer Medicine Design , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Shenping
authors.initials: S
authors.lastname: Liu
authors.affiliation: Pfizer Medicine Design , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: David
authors.initials: D
authors.lastname: Gebhard
authors.affiliation: Pfizer Drug Safety R&D , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: James E
authors.initials: JE
authors.lastname: Finley
authors.affiliation: Pfizer CVMET Biology , Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Salatto
authors.affiliation: Pfizer Medicine Design , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Amanda
authors.initials: A
authors.lastname: King-Ahmad
authors.affiliation: Pfizer Medicine Design , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Stock
authors.affiliation: Pfizer Medicine Design , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Karen
authors.initials: K
authors.lastname: Atkinson
authors.affiliation: Pfizer CVMET Biology , Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Reidich
authors.affiliation: Pfizer Medicine Design , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Wen
authors.initials: W
authors.lastname: Lin
authors.affiliation: Pfizer Medicinal Sciences , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Pfizer Medicine Design , Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Meihua
authors.initials: M
authors.lastname: Tu
authors.affiliation: Pfizer Medicine Design , Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Elnaz
authors.initials: E
authors.lastname: Menhaji-Klotz
authors.affiliation: Pfizer Medicine Design , Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.affiliation: Pfizer Medicine Design , Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Spiros
authors.initials: S
authors.lastname: Liras
authors.affiliation: School of Chemistry & Biochemistry, Georgia Institute of Technology , 901 Atlantic Avenue, Atlanta, Georgia 30332, United States.|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.
authors.forename: M G
authors.identifier: 0000-0001-8247-3108
authors.initials: MG
authors.lastname: Finn
authors.affiliation: Pfizer Medicine Design , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Vincent
authors.initials: V
authors.lastname: Mascitti
mesh_terms: D037263:Asialoglycoprotein Receptor / Q000378:metabolism*; D001643:Bridged Bicyclo Compounds / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004337:Drug Carriers / Q000737:chemistry; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007659:Ketones / Q000737:chemistry* / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D011108:Polymers / Q000737:chemistry* / Q000378:metabolism
chemical_list: D037263:Asialoglycoprotein Receptor; D001643:Bridged Bicyclo Compounds; D004337:Drug Carriers; D007659:Ketones; D011108:Polymers