论文标题

用于优化mRNA设计的算法可提高稳定性和免疫原性

Algorithm for Optimized mRNA Design Improves Stability and Immunogenicity

论文作者

Zhang, He, Zhang, Liang, Lin, Ang, Xu, Congcong, Li, Ziyu, Liu, Kaibo, Liu, Boxiang, Ma, Xiaopin, Zhao, Fanfan, Yao, Weiguo, Li, Hangwen, Mathews, David H., Zhang, Yujian, Huang, Liang

论文摘要

Messenger RNA(mRNA)疫苗被用于COVID-19,但仍遭受mRNA不稳定性和降解的关键问题,这是疫苗储存,分布和功效的主要障碍。先前的工作表明,优化二级结构稳定性会延长mRNA半衰期,而mRNA半衰期与最佳密码子一起增加了蛋白质的表达。因此,原则上的mRNA设计算法必须优化结构稳定性和密码子的使用,以提高mRNA效率。但是,由于代名词的密码子,mRNA设计空间非常大,例如,对于SARS-COV-2峰值蛋白,有$ \ sim \!10^{632} $ mRNA,这对以前的方法构成了无法克服的挑战。在这里,我们通过将其减少到计算语言学中的经典问题来为这个严重问题提供了一个简单的简单解决方案,在该问题中,发现最佳mRNA类似于在类似的声音替代方案中找到最可能的句子。我们的算法(名为LinearDesign)仅需11分钟即可到达峰值蛋白,并且可以共同优化稳定性和密码子使用情况。在实验上,在没有化学修饰的情况下,我们的设计在体外显着改善了mRNA的半衰期和蛋白质表达,并且与密码子优化的基准相比,抗体反应将抗体反应提高了23 $ \ times $ in Vivo。我们的工作可以探索以前无法达到的高度稳定和高效的设计,不仅是疫苗的及时工具,而且对于编码所有治疗蛋白的mRNA药物(例如,单克隆抗体和抗癌药物)。

Messenger RNA (mRNA) vaccines are being used for COVID-19, but still suffer from the critical issue of mRNA instability and degradation, which is a major obstacle in the storage, distribution, and efficacy of the vaccine. Previous work showed that optimizing secondary structure stability lengthens mRNA half-life, which, together with optimal codons, increases protein expression. Therefore, a principled mRNA design algorithm must optimize both structural stability and codon usage to improve mRNA efficiency. However, due to synonymous codons, the mRNA design space is prohibitively large, e.g., there are $\sim\!10^{632}$ mRNAs for the SARS-CoV-2 Spike protein, which poses insurmountable challenges to previous methods. Here we provide a surprisingly simple solution to this hard problem by reducing it to a classical problem in computational linguistics, where finding the optimal mRNA is akin to finding the most likely sentence among similar sounding alternatives. Our algorithm, named LinearDesign, takes only 11 minutes for the Spike protein, and can jointly optimize stability and codon usage. Experimentally, without chemical modification, our designs substantially improve mRNA half-life and protein expression in vitro, and dramatically increase antibody response by up to 23$\times$ in vivo, compared to the codon-optimized benchmark. Our work enables the exploration of highly stable and efficient designs that are previously unreachable and is a timely tool not only for vaccines but also for mRNA medicine encoding all therapeutic proteins (e.g., monoclonal antibodies and anti-cancer drugs).

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