PSMA-Targeted Nucleic Acid Conjugates via Click Chemistry
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Solution Overview
Problem
Existing methods for producing nucleic acid conjugates, such as those used in Givosiran, suffer from poor flexibility, complicated operations, and limited production scale, and there is a need for improved delivery of therapeutic siRNA into prostate cancer tissues/cells.
Innovation Solution
A conjugate is formed by covalently linking an azido-modified targeting ligand, such as KUE or DUPA, to a propargyl-modified small nucleic acid sequence using copper-catalyzed click chemistry, enabling efficient and rapid synthesis of nucleic acid conjugates with high targeting and activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If solid-phase synthesis method is used to produce nucleic acid conjugates, then the method is established and can be used, but the flexibility is poor, operation is complicated, and production scale is limited
Solution Approach 1:
The invention divides the conjugate synthesis into separate modular components: a pre-synthesized nucleic acid sequence with a terminal functional group and a separate ligand with a complementary functional group. These modules can be independently designed, synthesized, and stored, then combined through click chemistry when needed. This segmentation enables flexible assembly of different nucleic acid-ligand combinations without requiring complete re-synthesis, directly addressing the poor flexibility and operational complexity of solid-phase methods.
Solution Approach 2:
The invention performs preliminary synthesis of the nucleic acid sequence with a terminal functional group (azido, alkynyl, or vinyl) before conjugation. This pre-modified nucleic acid can be synthesized using standard automated oligonucleotide synthesis and then stored for later use. When a specific conjugate is needed, only the ligand portion requires synthesis and attachment via click chemistry, significantly simplifying operations compared to synthesizing the entire conjugate from scratch using solid-phase methods.
2Productivity
If conventional conjugation methods are used, then the process is established, but the synthesis efficiency is unsatisfactory and production scale is limited
Solution Approach 1:
The invention replaces conventional mechanical conjugation methods (such as amide bond formation requiring activation, protection/deprotection steps, and purification) with click chemistry reactions. The copper-catalyzed azide-alkyne cycloaddition or strain-promoted azide-alkyne cycloaddition provides rapid, high-yield conjugation under mild conditions without requiring complex mechanical intervention or extensive purification, dramatically improving synthesis efficiency and reducing time loss.
Solution Approach 2:
The invention utilizes changes in chemical parameters (introduction of azido, alkynyl, or vinyl functional groups) to enable rapid conjugation through click chemistry. These functional groups allow the reaction to proceed under mild conditions with high efficiency and specificity, transforming a previously time-consuming and low-yield process into a rapid, high-efficiency synthesis method that can be scaled up for production.
3Reliability
If the existing nucleic acid conjugate structure is used, then the basic function is achieved, but the targeting specificity and activity are insufficient
Solution Approach 1:
The invention introduces specific functional groups (azido, alkynyl, or vinyl) at the terminal position of the nucleic acid sequence to enable selective conjugation with PSMA-targeting ligands. This localized modification at a specific position (3'- or 5'-end) maintains the overall structure and function of the nucleic acid while adding targeted binding capability through the ligand portion, thereby improving targeting specificity without compromising conjugate activity.
Solution Approach 2:
The invention creates a composite structure combining nucleic acid (siRNA or antisense oligonucleotide) with PSMA-targeting ligands (such as KUE or DUPA derivatives) through click chemistry. This composite material integrates the gene-silencing function of the nucleic acid with the cell-targeting function of the ligand, achieving both high targeting specificity to PSMA-expressing cells and high biological activity for treating prostate cancer and other PSMA-positive diseases.
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 method allows for flexible and efficient synthesis of nucleic acid conjugates with high specific recognition, gene silencing performance, and tumor cell inhibition, applicable to targeted delivery of RNAi therapeutic reagents for diseases related to PSMA expression in glandular tissues.
Implementation Method 1
A conjugate is formed by covalently linking an azido-modified targeting ligand, such as KUE or DUPA, to a propargyl-modified small nucleic acid sequence using copper-catalyzed click chemistry
Data Source
AI summary
The disclosure relates to the field of biotechnology, discloses a conjugate, preparation method thereof and use thereof. The conjugate is formed by covalently linking an azido-modified targeting ligand to a propargyl-modified small nucleic acid sequence. The conjugate provided in the present disclosure has broad application prospects in drug targeted delivery. In addition, the present invention also provides a preparation method for the conjugate and a use thereof. The method only relates to simple chemical reactions, can achieve the purpose of flexibly and efficiently synthesizing a nucleic acid conjugate, is suitable for constructing other ligand-targeted nucleic acid conjugates, and has relatively of good practicability.