Issue 2, 2025

Synthesis of LNA gapmers that replace a phosphorothioate linkage with a sulfonamide in the gap region, and their ability to form duplexes with complementary RNA targets

Abstract

Antisense oligodeoxynucleotides can bind to target RNAs and cleave them using RNase H. Despite the high activity of antisense oligodeoxynucleotides modified with locked nucleic acids (LNA) at several bases at both the 5′ and 3′ ends (LNA gapmer), toxicity has been reported, necessitating additional backbone modifications to reduce toxicity. In this study, we introduced a sulfonamide linkage into the LNA gapmer to elucidate its fundamental properties such as hybridization, base recognition, and induction of RNase H activity. A new chemically stable sulfonyltriazole was used as a synthetic intermediate to introduce a sulfonamide linkage between the two nucleosides. We studied the properties of the duplex of the sulfonamide-linked gapmer and target RNAs, such as melting temperature, circular dichroism, and cleavage of RNA strands by RNase H. We found that the gapmers had a lower but tolerable duplex stability with base-pair specificity and the ability to induce RNase H activity.

Graphical abstract: Synthesis of LNA gapmers that replace a phosphorothioate linkage with a sulfonamide in the gap region, and their ability to form duplexes with complementary RNA targets

Supplementary files

Article information

Article type
Paper
Submitted
16 Aug 2024
Accepted
31 Oct 2024
First published
21 Nov 2024

Org. Biomol. Chem., 2025,23, 400-409

Synthesis of LNA gapmers that replace a phosphorothioate linkage with a sulfonamide in the gap region, and their ability to form duplexes with complementary RNA targets

K. Seio, R. Ohnishi, S. Tachibana, H. Mikagi and Y. Masaki, Org. Biomol. Chem., 2025, 23, 400 DOI: 10.1039/D4OB01350F

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