Fatty Acid Conjugates for Nucleic Acid Half-Life Extension
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Solution Overview
Problem
Current nucleic acid-based therapeutics face challenges in enhancing in vivo stability, half-life, clearance, and tissue distribution, which limits their therapeutic efficacy.
Innovation Solution
Development of novel fatty acid conjugates for nucleic acid molecules, specifically aptamers and small RNA molecules, where fatty acid moieties are covalently conjugated to the nucleic acid moiety to modify their properties, such as half-life and binding affinity to human serum albumin.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If nucleic acid-based therapeutics are administered, then therapeutic efficacy is achieved, but in vivo stability and half-life are insufficient
Solution Approach 1:
The patent applies composite materials by conjugating fatty acid moieties to nucleic acid molecules to create a hybrid structure that combines the therapeutic properties of nucleic acids with the stability and albumin-binding properties of fatty acids. This composite approach resolves the contradiction by extending half-life while maintaining in vivo stability, as demonstrated by the prolonged circulation time of fatty acid-conjugated aptamers compared to unmodified nucleic acids.
2Duration of action of stationary object
If fatty acid conjugates are used to extend half-life, then therapeutic efficacy is improved, but binding affinity to target may be affected
Solution Approach 1:
The patent applies local quality by strategically placing fatty acid conjugations at specific positions on the nucleic acid molecule (e.g., 5' or 3' ends) rather than throughout the entire structure. This localized modification allows the fatty acid moiety to extend half-life through albumin binding while preserving the critical target-binding regions of the nucleic acid, thus resolving the contradiction between extended circulation time and maintained binding affinity.
3Reliability
If chemical modifications are incorporated into nucleic acids, then nuclease resistance is enhanced, but pharmacokinetic properties may be compromised
Solution Approach 1:
The patent merges two separate modification strategies: nucleic acid chemical modifications (for nuclease resistance) and fatty acid conjugation (for improved pharmacokinetics). By combining these approaches, the invention achieves both enhanced nuclease resistance through modified nucleosides and improved pharmacokinetic properties through fatty acid-mediated albumin binding and extended half-life, thus resolving the contradiction between stability and pharmacokinetic performance.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The conjugation of fatty acid moieties extends the half-life of nucleic acid therapeutics in vivo, improving their stability and distribution, thereby enhancing their therapeutic efficacy.
Implementation Method 1
The presence of the 18-carbon fatty acid moiety results in a high binding affinity for serum albumin
Data Source
AI summary
The present disclosure relates to a conjugate comprising a fatty acid moiety and a nucleic acid moiety wherein the fatty acid moiety is conjugated to the nucleic acid via a polyethylene glycol (PEG) and a glutamic acid group. The nucleic acid moiety can be an aptamer or a variant thereof, an oligonucleotide, an antisense oligonucleotide, a CpG oligonucleotide, and a therapeutic RNA such as mRNA, siRNA, shRNA, microRNA, lncRNA, saRNA, circular RNA and the like. Methods for manufacturing the conjugates and use thereof are also provided.