Bivalent targeted conjugates

Abstract

The invention provides conjugates that comprise a bivalent targeting moiety, a nucleic acid, and optional linking groups as well as synthetic intermediates and synthetic methods useful for preparing the conjugates, compositions comprising the bidentate targeting ligands and the conjugates, as well as methods for targeting therapeutic nucleic acids with the bidentate conjugates. The conjugates are useful to target therapeutic nucleic acids.

Description

[0001] Cross References to Related Applications [0002] This patent claims priority to U.S. Application No. 62 / 755,179, filed November 2, 2018, which is incorporated herein by reference. Background technique [0003] Since the seminal paper by Ashwell and Morell elucidating the role of the asialoglycoprotein receptor (ASGPr) in the recognition and transport of circulating glycoproteins, this receptor has been the focus of intensive research (D'Souza et al., 2015, J. Control Release, 203, 126-139). High level expression on the surface of hepatocytes makes this receptor an attractive target for liver-specific delivery agents. The receptor has a trivalent carbohydrate binding domain that selectively binds N-acetylgalactosamine. A generally accepted rule is that binding affinity for a targeting ligand increases with the number of GalNac units in the following order: six GalNac units greater than four GalNac units, four GalNac units greater than three GalNac units, three GalNac ...

AI Technical Summary

Problems solved by technology

Increases in targeting ligand size (number of monosaccharide units, molecular weight, molecular radius, etc.) can adversely affect loading efficiency on supports

Therefore, there is an ongoing need for targeting ligands that have useful delivery properties but are easier to prepare, less expensive to prepare, lower molecular weight, and / or have higher loading efficiencies

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