Search

CN-122029177-A - Oligonucleotides containing multiple ligands and/or lipids

CN122029177ACN 122029177 ACN122029177 ACN 122029177ACN-122029177-A

Abstract

The present disclosure provides oligonucleotides comprising two or more groups of ligands and/or lipids conjugated at least one position on the oligonucleotide. The disclosure also provides pharmaceutical compositions and kits comprising the oligonucleotides, methods of delivering the oligonucleotides, methods of modulating protein activity using the oligonucleotides, and methods of treating, preventing, or diagnosing a disease (e.g., central nervous system disease, neurodegenerative disease, and neurocognitive disease) in a subject in need thereof using the oligonucleotides or pharmaceutical compositions thereof.

Inventors

  • LI ZHEN
  • ZHU RUI
  • Chandra Munli Cheruta

Assignees

  • 阿达尔克斯制药有限公司

Dates

Publication Date
20260512
Application Date
20240816
Priority Date
20230817

Claims (20)

  1. 1. An oligonucleotide comprising a modified oligonucleotide strand of formula I: (I), Or a salt or prodrug thereof, wherein: is a divalent group of an oligonucleotide chain; s1 instances of internucleoside linkers are independently Replacement; s1 is 0,1, 2, 3, 4, 5 or 6; When present, each instance of y4 is independently 0, 1,2, 3, 4, 5, or 6, and each of y5 and y6 is independently 0, 1,2, 3, 4, 5, or 6, provided that at least one of y4, y5, and y6 is 2, 3, 4, 5, or 6; when present, each instance of L A is independently a linker; each of a 4 、A 5 and a 6 , if present, is independently a group of a ligand or lipid; When (when) Examples of (2) are When L 4 is hydrogen, substituted or unsubstituted C 1-6 alkyl or an oxygen protecting group when attached to an oxygen atom, or when Examples of (2) are When the L 4 is a joint; L 5 is hydrogen, substituted or unsubstituted C 1-6 alkyl or an oxygen protecting group when attached to an oxygen atom when y5 is 0, or L 5 is a linker when y5 is 1,2, 3, 4,5 or 6, and L 6 is hydrogen, substituted or unsubstituted C 1-6 alkyl or an oxygen protecting group when attached to an oxygen atom when y6 is 0, or L 6 is a linker when y6 is 1, 2, 3,4, 5 or 6.
  2. 2. The oligonucleotide of claim 1, further comprising an antisense oligonucleotide strand, wherein Is a divalent group of the sense oligonucleotide strand.
  3. 3. The oligonucleotide of claim 1 or 2, further comprising a sense oligonucleotide strand, wherein Is a divalent group of an antisense oligonucleotide strand.
  4. 4. The oligonucleotide of claim 1, wherein Comprising between 6 and 100 nucleosides (inclusive).
  5. 5. The oligonucleotide of claim 1, wherein Comprising between 10 and 30 nucleosides (inclusive).
  6. 6. The oligonucleotide of claim 1, wherein Comprising between 14 and 23 nucleosides (inclusive).
  7. 7. The oligonucleotide of any one of claims 1-6, wherein the oligonucleotide comprises RNA.
  8. 8. The oligonucleotide of any one of claims 1-7, wherein the oligonucleotide is RNA.
  9. 9. The oligonucleotide of any one of claims 1-8, wherein Is siRNA.
  10. 10. The oligonucleotide of any one of claims 1-9, wherein s1 is 0.
  11. 11. The oligonucleotide of any one of claims 1-10, wherein: s1 is 1,2, 3, 4, 5 or 6, and At least one example of y4 is 2, 3, 4, 5 or 6.
  12. 12. The oligonucleotide of any one of claims 1-11, wherein At least two examples of a 4 of at least one example of (a) are groups of a ligand.
  13. 13. The oligonucleotide of any one of claims 1-12, wherein At least two examples of a 4 of at least one example of (a) are at least one group of a ligand and at least one group of a lipid.
  14. 14. The oligonucleotide of any one of claims 1-13, wherein At least two examples of a 4 of at least one example of (a) are groups of a lipid.
  15. 15. The oligonucleotide of any one of claims 1-14, wherein: When present, at least one example of L A has the formula: ; Each instance of Z A1 and Z A2 is independently a single bond, a substituted or unsubstituted C 1-6 alkylene group, or a substituted or unsubstituted C 2-6 alkenylene group; Each instance of W A is independently a substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene 、-O-、-OP(=O)(OR c )O-、-N(R c )-、-S-、-C(=O)-、-C(=O)O-、-C(=O)NR c -、-NR c C(=O)-、C(=O)R c -、-NR c C(=O)O-、-NR c C(=O)NR c -、-OC(=O)-、-OC(=O)O-、-OC(=O)N(R c )-、-S(=O) 2 NR c -、-NR c S(=O) 2 -, or a combination thereof, where the valency permits; Each instance of R c is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, nitrogen protecting group when attached to a nitrogen atom, or oxygen protecting group when attached to an oxygen atom, or two instances of R C are joined to form a substituted or unsubstituted heterocyclyl ring or a substituted or unsubstituted heteroaryl ring, and Bond C 4A is attached to L 4 .
  16. 16. The oligonucleotide of any one of claims 1-15, wherein at least one instance of L A when present has the formula: Or (b) 。
  17. 17. The oligonucleotide of any one of claims 1-16, wherein at least one instance of L A when present has the formula: 。
  18. 18. the oligonucleotide of any one of claims 1-17, wherein Z A1 is unsubstituted C 1-3 alkylene.
  19. 19. The oligonucleotide of any one of claims 1-18, wherein Z A2 is unsubstituted C 1-3 alkylene.
  20. 20. The oligonucleotide of any one of claims 1-19, wherein at least one instance of L A when present has the formula: 、 、 、 、 Or (b) 。

Description

Oligonucleotides containing multiple ligands and/or lipids RELATED APPLICATIONS The application is based on 35 U.S. C.119 (E) priority of U.S. S. N. 63/520,339, U.S. provisional application No. U.S. 8/17, filed 2023, the contents of which are incorporated herein by reference. Background In therapeutic, prophylactic or diagnostic applications using compounds (e.g., oligonucleotides), it is often desirable to deliver the compound to a particular location (e.g., to a desired cell, to a desired organ or tissue, or to a particular location in a subject) to enhance therapeutic or prophylactic effects or to facilitate diagnostic purposes. This is often the case when attempting to deliver therapeutic compounds in vivo. Furthermore, being able to effectively deliver a compound to a particular location may limit or potentially eliminate unexpected consequences (such as off-target effects) that may result from administration of the compound. One strategy that facilitates the in vivo delivery of a compound (such as a therapeutic, prophylactic or diagnostic compound) to a desired location is to link or attach the compound to a targeting ligand. One class of compounds that can be targeted using targeting ligands are oligomeric compounds, such as, for example, proteins, peptides, antibodies, and oligonucleotides. Oligomeric compounds (e.g., oligonucleotides) comprising nucleotide sequences at least partially complementary to a target nucleic acid have been demonstrated to alter the function and activity of the target in vitro and in vivo. Oligonucleotides have been demonstrated to modulate expression or activity of a target nucleic acid when delivered to cells containing the target nucleic acid, such as mRNA or pre-mRNA. In some cases, the oligonucleotides can reduce expression of a gene by inhibiting translation of a nucleic acid target and/or triggering degradation of the target nucleic acid. If the target nucleic acid is mRNA, one mechanism by which the oligonucleotide can modulate mRNA target expression is by RNA interference. RNA interference is a biological process by which RNA or RNA-like compounds, such as chemically modified RNA compounds, can be used to silence gene expression at least in part through the RNA-induced silencing complex (RISC) pathway. In addition, oligonucleotides can modulate expression of a target nucleic acid (such as a target mRNA) by an rnase recruitment mechanism, a microrna mechanism, an occupancy-based mechanism, and an editing mechanism. The oligonucleotides may be single-stranded or double-stranded. Oligonucleotides may include DNA, RNA, and RNA-like compounds, which may also comprise modified nucleosides that include one or more modified sugars, modified nucleobases, and modified internucleoside linkages. There is a need for new compounds for delivering agents (e.g., therapeutic, prophylactic, and diagnostic agents) to a subject. Disclosure of Invention In one aspect, the present disclosure provides an oligonucleotide comprising an oligonucleotide strand comprising two or more groups of ligands and/or lipids in one position. In one aspect, the disclosure relates to an oligonucleotide comprising a modified oligonucleotide chain of formula I: (I), Or a salt or prodrug thereof, wherein: is a divalent group of an oligonucleotide chain; s1 instances of internucleoside linkers are independently Replacement; s1 is 0,1, 2, 3, 4, 5 or 6; When present, each instance of y4 is independently 0, 1,2, 3, 4, 5, or 6, and each of y5 and y6 is independently 0, 1,2, 3, 4, 5, or 6, provided that at least one of y4, y5, and y6 is 2, 3, 4, 5, or 6; when present, each instance of L A is independently a linker; each of a 4、A5 and a 6, if present, is independently a group of a ligand or lipid; When (when) Examples of (2) areWhen L 4 is hydrogen, substituted or unsubstituted C 1-6 alkyl or an oxygen protecting group when attached to an oxygen atom, or whenExamples of (2) areWhen the L 4 is a joint; L 5 is hydrogen, substituted or unsubstituted C 1-6 alkyl or an oxygen protecting group when attached to an oxygen atom when y5 is 0, or L 5 is a linker when y5 is 1,2, 3, 4,5 or 6, and L 6 is hydrogen, substituted or unsubstituted C 1-6 alkyl or an oxygen protecting group when attached to an oxygen atom when y6 is 0, or L 6 is a linker when y6 is 1, 2, 3,4, 5 or 6. The oligonucleotide comprises two or more groups of ligands and/or lipids conjugated at least one position on the oligonucleotide (e.g., the 5 'end of the oligonucleotide, the 3' end of the oligonucleotide, or an internal position on the oligonucleotide). In some embodiments, the oligonucleotide further comprises one or more groups of ligands and/or lipids at one or more additional positions on the oligonucleotide. The oligonucleotides can be used to deliver an agent to a subject (e.g., a human). In some embodiments, at least one example of an agent is an oligonucleotide strand. In some embodiments, the ligand is capable of selectively targeting a locatio