Seminarium CeNT (06.06.2025): Chemistry based mRNA design enhancing translation toward therapeutics
02 06 2025
Kategoria: Seminaria CeNT, Strona główna
Centrum Nowych Technologii Uniwersytetu Warszawskiego zaprasza na seminarium:
Professor Hiroshi Abe
Department of Chemistry, Graduate School of Science, Nagoya University, Japan.
Tytuł: Chemistry based mRNA design enhancing translation toward therapeutics
Data: 06.06.2025, Piątek
Godzina: 12:00 (czasu środkowoeuropejskiego)
Gospodarz: prof. Jacek Jemielity
Seminarium odbędzie się w auli 00.142 im. prof. Piotra Węgleńskiego
Abstrakt:
mRNA production has traditionally relied on biological transcription reactions, yet chemical modification approaches offer new opportunities to optimize mRNA functionality. Modifications such as the incorporation of methylpseudouridine to mitigate immune stimulation, alteration of the poly(A) tail to improve stability and translation, and chemically modified cap structures have been widely explored. In our previous work, we developed the PureCap method, which employs a hydrophobic tag on a cap analog for efficient reversed-phase HPLC purification of mRNA, yielding high-purity products 3 . However, site-specific modifications remain challenging with enzymatic transcription, prompting the development of complete chemical synthesis methods. Using a nucleic acid synthesizer, we achieved 5′-phosphorylated RNA synthesis and high-efficiency capping with a novel reagent, enabling the total chemical synthesis of mRNA 1,2 . To overcome limitations of conventional designs, we recently advanced an internal cap-initiated translation (ICIT) strategy for circular mRNA. In this approach, an m7G cap is introduced internally, either via covalent attachment onto a branched RNA element (cap-circ mRNA) or by non-covalent tethering using an m7G-modified complementary oligonucleotide (cORN). Both strategies dramatically enhance translation efficiency, with cap-circ mRNA achieving up to 10^3-fold higher protein expression than uncapped variants. Moreover, when combined with N1-methylpseudouridine modification, these constructs exhibit robust, durable protein synthesis in cells and in vivo while minimizing innate immune activation 4.
Overall, our integrated approach—combining chemical synthesis, site- specific modifications, and innovative ICIT strategies—provides a versatile platform for next-generation mRNA therapeutics. This strategy not only enhances translational efficiency and mRNA stability but also reduces immunogenicity, making it a promising candidate for applications such as mRNA vaccines and cancer immunotherapies.
References:
1. Kawaguchi, D., Kodama, A., Abe, N., Takebuchi, K., Hashiya, F., Tomoike, F., Nakamoto, K., Kimura, Y., Shimizu, Y., & Abe, H. Phosphorothioate modification of mRNA accelerates the rate of translation initiation to provide more efficient protein synthesis. Angewandte Chemie International Edition 2020, 59(40), 17403-17407
2. Abe, N., Imaeda, A., Inagaki, M., Li, Z., Kawaguchi, D., Onda, K., Nakashima, Y., Uchida, S., Hashiya, F., Kimura, Y., & Abe, H. Complete Chemical Synthesis of Minimal Messenger RNA by Efficient Chemical Capping Reaction. ACS Chem. Biol. 2022, 17(6), 1308-1314.
3. Inagaki, M., Abe, N., Li, Z., Nakashima, Y., Acharyya, S., Ogawa, K., Kawaguchi, D., Hiraoka, H., Banno, A., Meng, Z., Tada, M., Ishida, T., Lyu, P., Kokubo, K., Murase, H., Hashiya, F., Kimura, Y., Uchida, S., & Abe, H. Cap analogs with a hydrophobic photocleavable tag enable facile purification of fully capped mRNA with various cap structures. Nat Commun. 2023 14(1), 2657.
4. Fukuchi, K.; Nakashima, Y.; Abe, N.; Kimura, S.; Hashiya, F.; Shichino, Y.; Liu, Y.; Ogisu, R.; Sugiyama, S.; Kawaguchi, D.; Inagaki, M.; Meng, Z.; Kajihara, S.; Tada, M.; Uchida, S.; Li, T.-T.; Maity, R.; Kawasaki, T.; Kimura, Y.; Iwasaki, S.; Abe, H. Internal Cap-Initiated Translation for Efficient Protein Production from Circular mRNA. Nat. Biotechnol. 2025, 1–13. https://doi.org/10.1038/s41587-025-02561-8.