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Publication Number
US-11672871-B2
Publication Date
2023-06-13
Expiration Date
Abstract
Provided herein are oligonucleotides, peptides, and peptide-oligonucleotide-conjugates. Also provided herein are methods of treating a muscle disease, a viral infection, or a bacterial infection in a subject in need thereof, comprising administering to the subject oligonucleotides, peptides, and peptide-oligonucleotide-conjugates described herein.
Core Innovation
The invention relates to a peptide-oligonucleotide-conjugate of Formula I, or a pharmaceutically acceptable salt thereof. The conjugate is defined by multiple interconnected variable groups including A′, E′, Q, R1, R2, L, J, G, M, and structural parameters such as z, t, d, and related chain-length selections. These variables control the identities of nucleobase-related components, peptide-related components, and linker-related components within the overall conjugate architecture.
The oligonucleotide-related portion includes R2 selected from H, a nucleobase, and a nucleobase functionalized with a chemical protecting-group, where the nucleobase comprises a C3-6 heterocyclic ring selected from pyridine, pyrimidine, triazinane, purine, and deaza-purine. A′, R5, R1, and E′ are selected from the stated substituent options, including terminal group and solid-support-linked variants, and z is selected within the claimed range. The disclosure also includes morpholino oligonucleotide (PMO) conjugates and PPMO conjugates, with Formula Ia-Ie and Formula IV/V variants.
A peptide portion is incorporated through J groups and a linker segment L covalently linked by an amide bond to the carboxy-terminus of J, and by covalent attachment of G to the amino-terminus of J. The peptide portion is defined by J selected from amino acids of a specified structure in which r and q each independently take values from 0 to 4, with R9 options that include amino acid side-chain and chemically protected amino acid side-chain residues, including sulfur-containing side-chain arrangements. M is selected from fluorinated aromatic structures, and the resulting conjugates are prepared and characterized.
Claims Coverage
The independent claim identified in the provided material is claim 1 / clm-00001, directed to a peptide-oligonucleotide-conjugate of Formula I, or a pharmaceutically acceptable salt thereof. The claim coverage centers on the Formula I framework with extensive variable structural definitions for the oligonucleotide portion, peptide portion, linker segment, and substituent selections, and the dependent claims narrow peptide identity, linker choices, numeric ranges, and selected substituent structures.
Peptide-oligonucleotide conjugate of Formula I
A peptide-oligonucleotide-conjugate of Formula I, or a pharmaceutically acceptable salt thereof, with defined variable selections for A′, R5, R1, R2, z, t, d, Q, G, E′, L, J, and M.
Oligonucleotide residue and length constraints
Each R1 is independently OH or —NR3R4 with R3 and R4 independently C1-6 alkyl; each R2 is independently H, a nucleobase, or a nucleobase functionalized with a chemical protecting-group; the nucleobase comprises a C3-6 heterocyclic ring selected from pyridine, pyrimidine, triazinane, purine, and deaza-purine; and z is within the claimed range.
Linkage architecture through L and G
L is covalently linked by an amide bond to the carboxy-terminus of J, and G is covalently linked to the amino-terminus of J, with L selected from the stated amide-containing alkylene-carbonyl structures and G selected from the stated substituent options.
Sulfur-containing peptide residue structure via J and R9
Each J is independently selected from an amino acid structure in which R9 is selected from H, an amino acid side-chain, and an amino acid side-chain functionalized with a chemical protecting-group, and two or more R9 side-chain groups comprise sulfur and form the stated sulfur-containing structure.
Defined length and terminal group parameters
The conjugate includes t as a peptide-length parameter, d as 0 or 1, E′ selected from H, C1-6 alkyl, C(O)C1-6 alkyl, benzoyl, stearoyl, trityl, monomethoxytrityl, dimethoxytrityl, and trimethoxytrityl, and M selected from fluorinated aromatic structures.
Peptide and linker architecture defined by Q and r/q
Q is —C(O)(CH2)6C(O)— or —C(O)(CH2)2S2(CH2)2C(O)—; L is selected from —NH(CH2)1-6C(O)— and —NH(CH2)1-6C(O)NH(CH2)1-6C(O)—; t is 4-9; and each J is independently at each occurrence selected from an amino acid structure wherein r and q are each independently 0, 1, 2, 3, or 4.
Overall, the claim coverage centers on a Formula I peptide-oligonucleotide conjugate with defined oligonucleotide-variable nucleobase selection and length, peptide-linker connectivity through L, J, and G, sulfur-containing peptide side-chain structure via R9, and additional constrained selections for Q, t, d, and M.
Stated Advantages
Stronger affinity for DNA/RNA without loss of sequence selectivity.
Reduced or prevented RNase H cleavage and RNase H activation.
Improved toxicity.
Improved pharmacokinetics.
Improved tissue distribution.
Improved cellular delivery.
Controllable in vivo distribution.
Enhanced cellular delivery/functional activity for peptide/PPMO conjugates versus unconjugated PMO.
Enhanced functional activity versus untreated cells in the HeLa eGFP exon skipping assay.
Documented Applications
Therapeutic treatment scope described for muscle disease, viral infection, and bacterial infection.
HeLa exon-skipping/cellular delivery assay with PPMOs.
In vivo mdx mouse testing reporting exon 23 skipping and dystrophin protein expression.
HeLa eGFP exon skipping assay using flow cytometer readouts (mean fluorescence intensity, mean FL1-H) to evaluate peptide/PPMO conjugates versus unconjugated PMO and untreated cells.
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