Scholarlink

<p>Despite the remarkable success of mRNA vaccines, improving the translational efficiency of mRNA therapeutics remains a critical challenge to their widespread clinical application. Here we systematically evaluate chemical modifications to improve the translational activity and stability of uncapped mRNA. We employ a primarily chemistry-based synthetic approach, which is crucial for the position-specific introduction of chemical modifications, enabling detailed structure-activity relationship studies, hitherto unattainable with conventional methods. A pivotal innovation herein is the introduction of 2´-F modification at the first nucleoside of the codon in the open reading frame, which significantly bolsters the stability of mRNA without compromising its translation. Additional modifications at the 5´-UTR and poly(A) tail with other types of nucleoside and phosphate analogs also exemplify the importance of terminal modifications for improved translation. Precise control of these modification patterns achieves higher peptide expression than conventional in vitro-transcribed mRNA. These findings offer a unique framework for designing effective mRNA-based therapeutics.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Position-specific ORF nucleoside-ribose modifications enabled by complete chemical synthesis enhance mRNA stability and translation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月19日

查看全文
  • Hiroto Iwai,
  • Yasuaki Kimura,
  • Masakazu Honma,
  • Kosuke Nakamoto,
  • Atsushi Hashimoto,
  • Keiichi Motosawa,
  • Takayuki Atago,
  • Kana Asano,
  • Fumitaka Hashiya,
  • Naoko Abe,
  • Keiko Kobayashi,
  • Ryoko Ogisu,
  • Hiroki Yamada,
  • Keiko Hiraishi,
  • Seiji Saito,
  • Junichiro Yamamoto,
  • Hiroshi Abe

摘要

Despite the remarkable success of mRNA vaccines, improving the translational efficiency of mRNA therapeutics remains a critical challenge to their widespread clinical application. Here we systematically evaluate chemical modifications to improve the translational activity and stability of uncapped mRNA. We employ a primarily chemistry-based synthetic approach, which is crucial for the position-specific introduction of chemical modifications, enabling detailed structure-activity relationship studies, hitherto unattainable with conventional methods. A pivotal innovation herein is the introduction of 2´-F modification at the first nucleoside of the codon in the open reading frame, which significantly bolsters the stability of mRNA without compromising its translation. Additional modifications at the 5´-UTR and poly(A) tail with other types of nucleoside and phosphate analogs also exemplify the importance of terminal modifications for improved translation. Precise control of these modification patterns achieves higher peptide expression than conventional in vitro-transcribed mRNA. These findings offer a unique framework for designing effective mRNA-based therapeutics.