Trialkyne linking agents and methods of use
Inventors
Li, Zhen • Altenhofer, Erich • Carlson, Jeffrey • Fowler-Watters, Matthew • Chen, Bo
Assignees
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Publication Number
US-12065458-B2
Publication Date
2024-08-20
Expiration Date
Abstract
Described are improved linking agents that are useful for facilitating the attachment of targeting groups, pharmacokinetic (PK) enhancers or modifiers, or other delivery agents to oligonucleotides. The described linking agents may exhibit improved reaction yields, stability, and biological activity, particularly when used in connection with oligonucleotide-based compounds, such as RNA interference (RNAi) agents.
Core Innovation
The disclosure provides trialkyne linking agents and related compounds for conjugating synthetic oligonucleotides, including RNA interference (RNAi) agents, to targeting ligands and/or other delivery agents. The linker chemistry uses defined linker components L1, L2, L3, and L4 with attachment-point notation and heteroatom selections X and Y as O or S, and includes pharmaceutically acceptable salts.
The structures include Formula I through Formula IX, including Formula III, Formula IV, Formula V, Formula VIII, and Formula IX, with selectable linker compositions such as optionally substituted alkylene, arylene, and cycloalkylene, and optional interruptions including PEG, amide, ether, ester, thioether, sulfone, and sulfonamide-type interruptions. The disclosure also includes targeting ligand substituents and RNA that comprises or consists of an RNAi agent.
The document further describes reaction-based formation of the disclosed conjugates, including reacting defined trialkyne linking-agent compounds with targeting ligands comprising azides and reacting Formula II with an RNAi agent to form Formula III. The examples and tables provide representative structures and embodiments, while the main emphasis remains on the defined linker architecture and the resulting TL-bearing and RNAi-agent-containing conjugates.
Claims Coverage
The independent claim coverage centers on three claim types: a compound of Formula III, a method of reacting Formula III with a targeting ligand comprising an azide to form Formula V, and a method of reacting Formula II with an RNAi agent to form Formula III. Across these claims, the inventive features are the defined linker systems L1-L4, attachment-point selection, heteroatom choices X as O or S and, for one method, Y as O or S, together with RNA comprising or consisting of an RNAi agent.
Formula III compound with defined linkers and RNAi agent
A compound of Formula III, or a pharmaceutically acceptable salt thereof, wherein L1, L2, and L3 are each linkers of the formula, L4 is selected from the group consisting of defined linker structures with an indicated point of attachment, R4 is H or optionally substituted alkyl, X is O or S, and RNA comprises or consists of an RNAi agent.
Azide targeting ligand reaction to form Formula V
A method of reacting a compound of Formula III with a targeting ligand (TL) comprising an azide to form a compound of Formula V, wherein L1, L2, and L3 are each linkers of the formula, L4 is selected from the group consisting of defined linker structures with an indicated point of attachment, R4 is H or optionally substituted alkyl, TL is a targeting ligand, X is O or S, Y is O or S, and RNA comprises or consists of an RNAi agent.
Reaction of Formula II with RNAi agent to form Formula III
A method of reacting a compound of Formula II with an RNAi agent to form a compound of Formula III, wherein L1, L2, and L3 are each linkers of the formula, L4 is selected from the group consisting of defined linker structures with an indicated point of attachment, each instance of R1 is optionally substituted alkyl, R2 is optionally substituted alkyl, R4 is H or optionally substituted alkyl, X is O or S, and RNA comprises or consists of an RNAi agent.
Overall, the claims cover defined trialkyne-linked RNAi conjugates and related reaction schemes, with the core inventive focus on the L1-L4 linker architecture, attachment-point notation, and specified heteroatom selections in combination with RNA comprising or consisting of an RNAi agent.
Stated Advantages
Higher yields.
Greater stability.
Fewer impurities.
Maintained or improved biological activity.
Documented Applications
Conjugation of synthetic oligonucleotides, including RNA interference (RNAi) agents, to targeting ligands and/or other delivery agents using trialkyne linking agents, including phosphoramidite trialkynes.
Conjugation involving targeting ligands (TL), including targeting ligands comprising azides, to form defined conjugate products within the disclosed formula sets.
Conjugation involving PK enhancers/modifiers as part of the delivery-agent context described in the disclosure.
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