A template-directed strategy enabled the synthesis of site-specifically modified long ssRNAs, demonstrating that m1Ψ modification on specific sites increases translation fidelity with low immunogenicity.
A novel template-directed strategy enables site-specific modification of long ssRNAs, demonstrating that specific m1Ψ modifications can increase translation fidelity with low immunogenicity, informing future mRNA drug design.
In the past few decades, RNA modifications have significantly promoted the development of mRNA therapy. However, limited knowledge has been revealed on the site-specific effect of the modification, which raised biosafety concerns on mis-modified or overmodified mRNA drugs. Here in this study, we proposed a template-directed strategy for the synthesis of site-specifically modified long ssRNA. Long single-strand RNAs (over 300 nt) with single-base resolution modifications have been successfully prepared, including m6A, m5C, m1Ψ, Ψ, I, Br–dU, Cy3, Cy5, FAM, 2’-F, 2’-OMe, 2’-MOE, 2’-Propargyl, LNA, cET, and PS modifications. Based on this method, the impact of the precisely modified patterns of mRNA on translation has been investigated. We have demonstrated that the modification of m1Ψ on specific sites could increase translation fidelity while retaining low immunogenicity. It can be anticipated that our study will provide a guideline for mRNA modification to precisely adjust their functions, which will further promote next-generation mRNA drugs and RNA epigenetics research.
Pan et al. (Thu,) reported a other. Template-directed strategy for the synthesis of site-specifically modified long ssRNA was evaluated on Impact of precisely modified patterns of mRNA on translation fidelity and immunogenicity. A template-directed strategy enabled the synthesis of site-specifically modified long ssRNAs, demonstrating that m1Ψ modification on specific sites increases translation fidelity with low immunogenicity.