Peptide docking vehicle for targeted nucleic acid delivery
Inventors
Lu, Xiaoyong • Lu, Patrick Y. • Evans, David M.
Assignees
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Publication Number
US-12054714-B2
Publication Date
2024-08-06
Expiration Date
Abstract
Peptide docking vehicle compositions containing a therapeutic compound, such as an siRNA molecule, and a targeting ligand are provided, together with methods for their preparation and use. The compositions and methods allow targeted cell/tissue delivery of the therapeutic compound to a subject by linking a targeting ligand to the compound to provide enhanced therapeutic benefit. The subject may be an animal or a human.
Core Innovation
The invention relates to a chemical construct comprising a peptide construct covalently linked to a targeting ligand and a first therapeutic oligonucleotide, with an optional second therapeutic oligonucleotide that may be the same or different than the first. The targeting ligand is linked to the side chain of a cysteine residue and the first oligonucleotide is linked to the side chain of a lysine residue. The amino acid sequence of the peptide construct is selected from a defined group of histidine/lysine-rich sequences.
The peptide sequences include KHHHCKH (SEQ ID NO: 3), HKHHHCKH (SEQ ID NO: 4), HHKHHHCKH (SEQ ID NO: 5), HHHKHHHKCHHHKHHH (SEQ ID NO: 6), HHHKHHCKHHH (SEQ ID NO: 7), HHHKHHCRHHH (SEQ ID NO: 8), HKHHCKH (SEQ ID NO: 9), HKHCH (SEQ ID NO: 10), HKHCKH (SEQ ID NO: 11), HKHC (SEQ ID NO: 12), HHHK(S)HHCKHHH (SEQ ID NO: 13), and HHK(S)HHKCHH(S)HHH (SEQ ID NO: 14). The targeting ligand includes GalNAc and other named ligand options, and the construct supports GalNAc-targeted oligonucleotide-peptide conjugates.
The document further includes covalent conjugation sites and linker chemistry for the construct. It includes linker options such as click-like Rs for coupling, ligand linkers RL that include triazole/PEG/amide/thioether linkages, and oligonucleotide linker/linker-2 defined by reactive Group 2 chemistry.
Claims Coverage
The independent claim covers a covalently linked chemical construct that combines a peptide construct, a targeting ligand, and a first therapeutic oligonucleotide, with an optional second therapeutic oligonucleotide. One independent claim is identified, and the dependent claims refine the targeting ligand options, the peptide sequence set, the therapeutic oligonucleotide types, and linker/reactive moiety features.
Covalent peptide-oligonucleotide construct with targeting ligand
A chemical construct comprising a peptide construct covalently linked to a targeting ligand and to a first therapeutic oligonucleotide, and optionally a second therapeutic oligonucleotide, wherein the targeting ligand is linked to the side chain of a cysteine residue and the first oligonucleotide is linked to the side chain of a lysine residue.
Defined peptide sequence set for the peptide construct
The amino acid sequence of the peptide construct is selected from a group of histidine/lysine-rich sequences including KHHHCKH (SEQ ID NO: 3), HKHHHCKH (SEQ ID NO: 4), HHKHHHCKH (SEQ ID NO: 5), HHHKHHHKCHHHKHHH (SEQ ID NO: 6), HHHKHHCKHHH (SEQ ID NO: 7), HHHKHHCRHHH (SEQ ID NO: 8), HKHHCKH (SEQ ID NO: 9), HKHCH (SEQ ID NO: 10), HKHCKH (SEQ ID NO: 11), HKHC (SEQ ID NO: 12), HHHK(S)HHCKHHH (SEQ ID NO: 13), and HHK(S)HHKCHH(S)HHH (SEQ ID NO: 14).
Targeting ligand options
The targeting ligand is selected from GalNAc and other named ligand options, including carbohydrate-type ligands and named peptide ligands.
Optional second therapeutic oligonucleotide
An optional second therapeutic oligonucleotide may be the same or different than the first.
Linker and reactive moiety features
The construct includes linker options such as click-like Rs for coupling, ligand linkers RL that include triazole/PEG/amide/thioether linkages, and oligonucleotide linker/linker-2 defined by reactive Group 2 chemistry.
The claim set centers on a peptide construct with a defined histidine/lysine-rich sequence covalently attached to a cysteine-linked targeting ligand and a lysine-linked therapeutic oligonucleotide, optionally with a second oligonucleotide. Dependent claims further define ligand options, peptide sequence variants, and linker/reactive moiety features.
Stated Advantages
Not explicitly described in patent.
Documented Applications
In vitro cell uptake studies in ASGPR-overexpressing HepG2/Huh7 cells showing GalNAc-dependent uptake specificity for PDoV1/2/3.
Binding-related readouts in primary mouse hepatocytes with a bDNA assay.
Sequential examples for ApoB100- and mTTR-derived conjugates, including ApoB100-PDoV1/2/3-GalNAc3 and dye-labeled variants such as Alexa-647 labeled conjugates.
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