Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12239715-B2
Publication Date
2025-03-04
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 disclosure provides peptide-oligonucleotide conjugates, including pharmaceutically acceptable salts, having a peptide-coupled oligonucleotide scaffold defined by Formula (I). The conjugates include variable structural groups defined within Formula (I), where z defines a backbone range and where R1 and R2 define substituent and nucleobase-related options, including nucleobases comprising pyridine, pyrimidine, triazinane, purine, or deaza-purine.
The peptide-oligonucleotide conjugates include peptide and linker-related moieties defined in the scaffold, including A′, E′, Q, and a linker/L-(J)t-G arrangement, with J/G peptide residue and an arginine-containing peptide component. The scaffold further defines E′ and Q options, and includes substituent selection for groups such as R5, R6, R7, R8, R10, and d, together with conditions under which at least one of the specified structural relationships is true.
The disclosure describes multiple labeled conjugate variants corresponding to substituted scaffold instances (Ia–Ie and IV–V). The conjugates are presented as improved peptide-oligonucleotide constructs intended to enhance DNA/RNA binding while minimizing RNase H cleavage and RNase H activation, and the disclosure further attributes peptide-driven improvements to lower toxicity and enhanced oligonucleotide activity, together with improved pharmacokinetics and tissue distribution, enhanced cellular delivery, and controllable in vivo distribution.
Claims Coverage
The independent claim set centers on a peptide-oligonucleotide conjugate of Formula (I) (or pharmaceutically acceptable salt). It combines an arginine-containing peptide architecture with oligonucleotide-related R2 options, peptide/linker moieties A′, E′, Q, and L-(J)t-G, and multiple structural conditions, including z, d, and defined substituent selections.
Peptide-oligonucleotide conjugate of Formula (I)
A peptide-oligonucleotide-conjugate, or a pharmaceutically acceptable salt thereof, defined by Formula (I), where z is 8–40 and R1, R2, A′, R5, R6, E′, Q, R7, R8, R11, and L-(J)t-G are selected according to the enumerated definitions, including nucleobase selections comprising pyridine, pyrimidine, triazinane, purine, or deaza-purine.
Nucleobase-containing oligonucleotide options in R2
Each R2 is independently selected from H, a nucleobase, and a nucleobase functionalized with a chemical protecting-group, where the nucleobase independently comprises pyridine, pyrimidine, triazinane, purine, or deaza-purine.
Arginine-containing peptide residue with L-(J)t-G
The scaffold includes L-(J)t-G, where R is arginine, d is 0 or 1, and the structure of L-(J)t-G is defined in combination with the peptide residue and the stated conditions, with substituent R10 selections (H or a halogen) as part of the defined residue architecture.
Linker/pendant moieties and conditions for A′ and E′
The scaffold includes A′ and E′ with enumerated selections for each, including A′ selected from -NHCH2C(O)NH2, -N(C1-6-alkyl)CH2C(O)NH2, and E′ selected from enumerated groups such as H, -C1-6alkyl, -C(O)C1-6alkyl, benzoyl, stearoyl, trityl, monomethoxytrityl, dimethoxytrityl, and trimethoxytrityl, together with the stated condition that at least one of the listed relationships involving A′/E′ and L-(J)t-G is true.
The independent claim centers on a peptide-oligonucleotide conjugate (or pharmaceutically acceptable salt) defined by Formula (I), combining a backbone parameter z, nucleobase-related R2 options, peptide/linker moieties A′, E′, Q, and L-(J)t-G, and an arginine-containing peptide residue architecture. The claim further requires at least one of the specified structural conditions involving A′ and E′ to be satisfied.
Stated Advantages
Enhanced cellular uptake and exon-skipping activity with dystrophin expression.
Improved DNA/RNA binding without loss of sequence selectivity.
Reduced/minimized RNase H cleavage and RNase H activation.
Lower toxicity.
Enhanced oligonucleotide activity.
Improved pharmacokinetics and tissue distribution.
Enhanced cellular delivery.
Controllable in vivo distribution.
Documented Applications
Oligonucleotides containing targeting sequences complementary to an RNA target, with embodiments described for sufficient complementarity or perfect complementarity.
Therapeutic administration for muscle disease (Duchenne muscular dystrophy).
Therapeutic administration for viral infections (Marburg virus, Ebola virus, influenza virus, and dengue virus).
Therapeutic administration for bacterial infections (Mycobacterium tuberculosis).
Cell delivery/activity described using HeLa assays with eGFP exon skipping readouts, including peptide/PMO conjugates compared to unconjugated PMO and untreated cells.
Exon-skipping assay in mdx mice.
Treating muscle diseases by administering the specified peptide-oligonucleotide conjugates.
Treating viral infections by administering the specified peptide-oligonucleotide conjugates.
Treating bacterial infections by administering the specified peptide-oligonucleotide conjugates.
Interested in licensing this patent?