Multivalent ligand clusters for targeted delivery of therapeutic agents
OwnerPengcheng Patrick SHAOinventor
Life of this patent
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Abstract
Targeting ligand clusters, and methods of preparing same, are described. A targeting ligand cluster may include first linkers attached to phenolic hydroxyl groups of gallic acid, and one or more targeting ligands attached to each of the first linkers. The targeting ligand cluster may also include a second linker attached to a carboxylic acid of the gallic acid, and at least one of a protecting group, a phosphoramidite, or an oligonucleotide attached to the second linker.
Claims27
A compound comprising a targeting ligand cluster of Formula 2
- wherein linkerA is independently selected and comprises at least one spacer, with one end of linkerA attaching to a GalNAc targeting ligand and the other end attaching to a phenolic hydroxy group of gallic acid through an ether bond;
- wherein linkerB is independently selected and comprises at least one spacer, with one end of linkerB attaching to a phosphorous atom of a phosphoramidite or an oligonucleotide and the other end attaching to the carboxylic acid of gallic acid through an amide bond;
- wherein Ra comprises a C1 to C6 alkyl, C3 to C6 cycloalkyl, an isopropyl group, or Ra is joined with Rb through a nitrogen atom to form a cycle;
- wherein Rb comprises a C1 to C6 alkyl, C3 to C6 cycloalkyl, an isopropyl group, or Rb is joined with Ra through a nitrogen atom to form a cycle;
- and
- wherein Rc comprises a phosphite and phosphate protecting group, or a 2-cyanoethyl group.
(canceled)
5-6. (canceled)
(canceled)
16-29. (canceled)
A compound comprising a targeting ligand cluster of Formula 1
- wherein TL is one or more targeting ligands, including but not limited to:
- N-acetylgalactosamine, galactose, galactosamine, N-formyl-galactosamine, N-propionylgalactosamine, N-n-butanoylgalactosamine, and N-iso-butanoylgalactosamine;
- wherein one or more TLs may be different from one or more other TLs of the same targeting ligand cluster;
- wherein linkerA is independently selected and comprises one or more bifunctional spacers, with one end of linkerA attaching to the targeting ligand and the other end attaching to a phenolic hydroxy group of gallic acid through an ether bond;
- wherein linkerB is independently selected and comprises a bifunctional spacer, with one end of linkerB attaching to a phosphoramidite or an oligonucleotide and the other end attaching to the carboxylic acid of gallic acid through an amide bond;
- and
- wherein W is H, a protecting group, phosphoramidite or oligonucleotide.
-64. (canceled)
66-68. (canceled)
A method of reducing expression of a target gene in a cell comprising:
- contacting a cell capable of expressing the target gene with a composition comprising the targeting ligand cluster of Formula 1
- wherein TL is one or more targeting ligands, including but not limited to:
- N-acetylgalactosamine, galactose, galactosamine, N-formyl-galactosamine, N-propionylgalactosamine, N-n-butanoylgalactosamine, and N-iso-butanoylgalactosamine;
- wherein one or more TLs may be different from one or more other TLs of the same targeting ligand cluster;
- wherein linkerA is independently selected and comprises one or more bifunctional spacers, with one end of linkerA attaching to the targeting ligand and the other end attaching to a phenolic hydroxy group of gallic acid through an ether bond;
- wherein linkerB is independently selected and comprises a bifunctional spacer, with one end of linkerB attaching to a phosphoramidite or an oligonucleotide and the other end attaching to the carboxylic acid of gallic acid through an amide bond;
- and
- wherein W is an oligonucleotide comprising an siRNA that reduces expression of the target gene.
70-77. (canceled)
Dependencies are inferred from the claim text.