General Platform for Efficient and Modular Assembly of GalNAc–siRNA Conjugates via Primary Amines and o-Nitrobenzyl Alcohol Cyclization Photoclick Chemistry Enabling Rapid Access to Therapeutic Oligonucleotides

JACS Au, Journal Year: 2025, Volume and Issue: 5(3), P. 1402 - 1412

Published: Feb. 24, 2025

Oligonucleotide-based therapies, especially ligand-conjugated siRNAs, offer significant therapeutic potential for a wide array of diseases. However, conventional solid-phase synthesis and current postsynthetic in-solution conjugation methods face notable challenges related to efficiency, accessibility, the scalability diverse ligand–oligonucleotide conjugates. Herein, we introduce novel strategy highly efficient, rapid, modular assembly GalNAc–siRNA conjugates based on light-induced primary amine o-nitrobenzyl alcohol cyclization (PANAC) chemistry. Leveraging advantages PANAC photoclick chemistry linkers, our method enables direct trivalent GalNAc (tGalNAc) with commercially available primary-amine-modified siRNAs. This approach demonstrates efficient rapid therapeutically relevant oligonucleotides ligands interest, offering operational simplicity practicality; thus, it effectively overcomes limitations existing methods. More importantly, developed siRNA–tGalNAc showed robust gene silencing effect superior parent siRNA conjugate, highlighting effectiveness in generating screening enhance vivo potency. Overall, oligonucleotide–tGalNAc using readily accessible tGalNAc-amine ligands. expands toolkit conjugates, providing general platform broad applicability, thereby advancing optimization development oligonucleotide-based therapeutics.

Language: Английский

Non-competitive Inhibition of Ag(I) Catalysis by Coenzyme A: A Novel Strategy for Detecting Histone Acetyltransferase Activity in Gastric Cancer Circulating Tumor Cells

Sensors and Actuators B Chemical, Journal Year: 2025, Volume and Issue: unknown, P. 137959 - 137959

Published: May 1, 2025

Language: Английский