Bicyclic peptide oligonucleotide conjugates
Inventors
Wolfe, Justin M. • Fadzen, Colin M. • Holden, Rebecca L. • Yao, Monica • Hanson, Gunnar J. • Pentelute, Bradley L.
Assignees
Massachusetts Institute of Technology • Sarepta Therapeutics Inc
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Publication Number
US-12502432-B2
Publication Date
2025-12-23
Expiration Date
Abstract
Provided herein are oligonucleotides, bicyclic 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 document describes peptide–oligonucleotide conjugates in which an oligonucleotide is covalently bound to a peptide. The conjugates are defined by Formula I, including Formula Ia and Formula Ib, and by multiple structural options for both the oligonucleotide portion and the peptide-linker attachment region.
The peptide conjugation architecture is specified through a linker L and a peptide segment involving a -L-(J)t-G portion. L is covalently linked by an amide bond to the amino-terminus of a cysteine residue, and G is covalently linked by an amide bond to the carboxy-terminus of J, with J independently selected from cysteine and arginine and t selected within stated ranges with a limiting condition on the sum.
The document further describes cyclic and bicyclic cysteine-containing peptide constructs and their conjugation to oligonucleotide components. It also states that these conjugates address performance and delivery limitations of unmodified oligonucleotides by providing a conjugate structure intended to improve antisense/antigene performance.
Claims Coverage
The independent claims are directed to peptide–oligonucleotide conjugates of Formula I, or pharmaceutically acceptable salts, with multiple structural limitations on the oligonucleotide and peptide portions. The claim coverage centers on a cysteine-linked linker L, a -L-(J)t-G architecture, terminal group selections, nucleobase options, and an oligonucleotide length parameter z of 8-40, with further refinements including linker, G, and composition limitations.
Formula I peptide–oligonucleotide conjugate
A peptide–oligonucleotide conjugate of Formula I, or a pharmaceutically acceptable salt thereof, having oligonucleotide terminal group selections A′ and E′, an oligonucleotide length parameter z of 8-40, nucleobase selections comprising a C3-6 heterocyclic ring selected from pyridine, pyrimidine, triazinane, purine, and deaza-purine, and peptide features including a covalent linker L connected via amide bonds to cysteine and a carboxy-terminal group G.
Covalent linker L to cysteine amino-terminus and -L-(J)t-G architecture
L is covalently linked by an amide bond to the amino-terminus of a cysteine residue and defines the -L-(J)t-G portion in which each J is independently selected from cysteine and arginine; each t is independently selected from stated ranges with a limiting condition on the sum, and the cysteine side-chain is represented in the structure.
Carboxy-terminus covalent attachment of G
G is covalently linked by an amide bond to the carboxy-terminus of J and is selected from H, -C(O)C1-6-alkyl, benzoyl, stearoyl, and C(O)CH3.
Terminal group A′ and E′ selection constraints
A′ is selected from each R1 independently selected from OH and -NR3R4 where each R3 and R4 are independently at each occurrence -C1-6-alkyl; E′ is selected from H, -C(O)CH3, benzoyl, stearoyl, trityl, and 4-methoxytrityl, wherein at least one of the stated conditions is true.
Pharmaceutical composition including the conjugate and a pharmaceutically acceptable carrier
A pharmaceutical composition including the compound of Formula I, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier.
Overall, the claim coverage centers on a precisely defined Formula I peptide–oligonucleotide conjugate incorporating an oligonucleotide length constraint, nucleobase and terminal-group selections, and a cysteine-linked peptide architecture with a -L-(J)t-G region. It also includes a pharmaceutical composition including a pharmaceutically acceptable carrier.
Stated Advantages
Improved cell penetration in high fractions of cells.
Up to ~10–20x uptake enhancement.
Improved splicing versus other CPPs.
Provides stronger DNA/RNA affinity compared with unmodified oligonucleotides.
Reduces RNase H cleavage and activation compared with unmodified oligonucleotides.
Shows lower toxicity compared with unmodified oligonucleotides.
Improves pharmacokinetics and tissue distribution.
Improves cellular delivery.
Enables controllable in vivo distribution.
Documented Applications
Methods for treating muscle disease, including Duchenne muscular dystrophy.
Methods for treating viral infections, including marburg, ebola, influenza, and dengue.
Methods for treating bacterial infection, including Mycobacterium tuberculosis.
Therapeutic use for muscle disease.
Therapeutic use for viral infection.
Therapeutic use for bacterial infection.
An in vivo eGFP-654 mouse experiment assessing antisense activity of peptide-PMO conjugates through fluorescence imaging and exon-splicing correction.
An LC-MS proteolysis assay readout methodology used in evaluating peptide-PMO conjugates.
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