NUCLEOTIDE-BASED ENHANCEMENT AGENT FOR RNA DELIVERY AND THERAPY
The present disclosure provides a Nucleotide-Based Enhancement Agent being a compound or a pharmaceutically acceptable salt thereof, comprising from 2 to 30 nucleotides, wherein each nucleotide independently is of Formula (I) or (II): pharmaceutically acceptable salts thereof, and related conjugates. The present disclosure also relates to uses of the Nucleotide-Based Enhancement Agents and conjugates, e.g., in delivering nucleic acid and/or treating or preventing diseases.
1 . A conjugate or a pharmaceutically acceptable salt thereof, comprising:
(i) one or more Nucleic Acid Agent;
(ii) one or more Ligand; and
(iii) one or more Nucleotide-Based Enhancement Unit, wherein each Nucleotide-Based Enhancement Unit independently comprises from 2 to 30 nucleotides, wherein each nucleotide independently is of:
wherein:
Nucleic Acid Agent comprises an oligonucleotide;
Ligand is a moiety that, when covalently attached to the Nucleic Acid Agent, is capable of mediating its entry into, or facilitating its delivery to, a target site;
the one or more Nucleic Acid Agent, one or more Ligand, and one or more Nucleotide-Based Enhancement Unit are covalently linked to one another either directly or via a Linker Unit;
B is H, C 1 -C 6 alkyl, or a nucleobase moiety;
V is —O—, —NR V —, or —C(R V ) 2 —;
each R V independently is H or C 1 -C 6 alkyl;
X is H, halogen, or —OR X ;
R X is H, C 1 -C 12 alkyl, or —(C 1 -C 6 alkyl)-(C 6 -C 10 aryl), wherein the C 1 -C 6 alkyl or —(C 1 -C 6 alkyl)-(C 6 -C 10 aryl) is optionally substituted with one or more R Xa ; or R X and R 4 together form C 1 -C 6 alkylene;
each R Xa independently is halogen, C 1 -C 6 alkyl, or —O—(C 1 -C 6 alkyl), wherein the C 1 -C 6 alkyl or —O—(C 1 -C 6 alkyl) is optionally substituted with one or more halogen;
Y is —P(R Y )—, —P(OR Y )—, —P(N(R Y ) 2 )—, —P(═O)(OR Y )—, —P(═O)(R Y )—, —P(═S)(OR Y )—, —P(═S)(R Y )—, —P(═O)(SR Y )—, or —P(═S)(SR Y )—;
each R Y independently is H or C 1 -C 6 alkyl optionally substituted with one or more halogen or cyano;
R 1 is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;
R 2 is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;
R 3 is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;
R 4 is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen; or R 4 and R X together form C 1 -C 6 alkylene;
each R 5 independently is H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more halogen;
each # independently denotes an attachment to the 2′- or 3′-position of another nucleotide of the Nucleotide-Based Enhancement Unit, or denotes H or an attachment to the rest of the conjugate when the nucleotide is at the 5′-end of the Nucleotide-Based Enhancement Unit; and
each ## independently denotes an attachment to the 5′-position of another nucleotide of the Nucleotide-Based Enhancement Unit, or denotes H or an attachment to the rest of the conjugate when the nucleotide is at the 2′- or 3′-end of the Nucleotide-Based Enhancement Unit.
2 . The conjugate of any one of the preceding claims , wherein at least one Nucleotide-Based Enhancement Unit comprises from 3 to 20 nucleotides.
3 . The conjugate of any one of the preceding claims , wherein at least one Nucleotide-Based Enhancement Unit comprises from 6 to 15 nucleotides.
4 . The conjugate of any one of the preceding claims , wherein at least one Nucleotide-Based Enhancement Unit comprises 9 nucleotides.
5 . The conjugate of any one of the preceding claims , wherein at least one Nucleotide-Based Enhancement Unit is attached to the Nucleic Acid Agent directly or via a Linker Unit.
6 . The conjugate of any one of the preceding claims , wherein at least one Nucleotide-Based Enhancement Unit is attached to the sense strand of the Nucleic Acid Agent directly or via a Linker Unit.
7 . The conjugate of any one of the preceding claims , wherein at least one Nucleotide-Based Enhancement Unit is attached to the 3′-end of the Nucleic Acid Agent directly or via a Linker Unit.
8 . The conjugate of any one of the preceding claims , wherein at least one Nucleotide-Based Enhancement Unit does not bind to any part of the antisense strand of the Nucleic Acid Agent.
9 . The conjugate of any one of the preceding claims , wherein at least one Nucleotide-Based Enhancement Unit is attached to a Ligand directly or via a Linker Unit.
10 . The conjugate of any one of the preceding claims , wherein at least one Nucleotide-Based Enhancement Unit is attached to:
(i) both the Nucleic Acid Agent and the Ligand directly;
(ii) the Nucleic Acid Agent directly and the Ligand via a Linker Unit;
(iii) the Ligand directly and the Nucleic Acid Agent via a Linker Unit; or
(iv) both the Nucleic Acid Agent and the Ligand via a Linker Unit.
11 . The conjugate of any one of the preceding claims , wherein the Nucleic Acid Agent is a double stranded RNA.
12 . The conjugate of any one of the preceding claims , wherein the conjugate has a structure described in FIG. 1 .
13 . The conjugate of any one of the preceding claims , wherein the conjugate has a structure described in Table D.
14 . The conjugate of any one of the preceding claims , wherein the conjugate has a structure described in Table C.
15 . The conjugate of any one of the preceding claims , wherein the ligand comprises a carbohydrate moiety.
16 . The conjugate of any one of the preceding claims , wherein the carbohydrate moiety comprises a monosaccharide, a disaccharide, a trisaccharide, or a tetrasaccharide.
17 . The conjugate of any one of the preceding claims , wherein the carbohydrate moiety comprises galactose or a derivative thereof.
18 . The conjugate of any one of the preceding claims , wherein the ligand comprises a moiety capable of binding to a glucagon-like peptide-1 receptor (GLP-1 receptor).
19 . The conjugate of any one of the preceding claims , wherein the ligand comprises glucagon-like peptide-1 (GLP-1) or a derivative thereof.
20 . The conjugate of any one of the preceding claims , wherein the ligand comprises glucagon or a derivative thereof.
21 . An isotopic derivative of the conjugate of any one of the preceding claims .
22 . A pharmaceutical composition comprising the conjugate of any one of the preceding claims .
23 . A method of modulating the expression of a target gene in a subject, comprising administering to the subject the conjugate of any one of claims 1-21 .
24 . A method of delivering a Nucleic Acid Agent to a subject, comprising administering to the subject the conjugate of any one of claims 1-21 .
25 . A method of treating or preventing a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the conjugate of any one of claims 1-21 .