Algorithm for optimized mRNA design improves stability and immunogenicity.
Algorithm for optimized mRNA design improves stability and immunogenicity.
复制标题
DOI：
10.1038/s41586-023-06127-z
复制
发表时间：
2023-09
期刊：
影响因子：
64.8
通讯作者：
Huang, Liang
中科院分区：
文献类型：
--
作者：
Zhang, He;Zhang, Liang;Lin, Ang;Xu, Congcong;Li, Ziyu;Liu, Kaibo;Liu, Boxiang;Ma, Xiaopin;Zhao, Fanfan;Jiang, Huiling;Chen, Chunxiu;Shen, Haifa;Li, Hangwen;Mathews, David H.;Zhang, Yujian;Huang, Liang
信使核糖核酸疫苗正被用来对抗新冠肺炎的传播。)，但它们仍然表现出由mRNA不稳定和降解引起的严重限制，这是疫苗产品储存、分配和效力的主要障碍。增加二级结构延长了mRNA的半衰期，与最佳密码子一起，改善了蛋白质的表达。因此，一个原则性的mRNA设计算法必须同时优化结构稳定性和密码子使用。然而，由于同义密码子，信使核糖核酸设计空间大得令人望而却步-例如，大约有2.4 × 10632候选信使核糖核酸序列用于SARS-CoV-2刺突蛋白。这带来了难以克服的计算挑战。在这里，我们使用计算语言学中的经典格子句法分析概念提供了一个简单而意想不到的解决方案，其中找到最优的mRNA序列类似于在发音相似的备选方案中识别最可能的句子。我们的算法LinearDesign在短短11分钟内找到了针对Spike蛋白质的最佳mRNA设计，并且可以同时优化稳定性和密码子的使用。与针对新冠肺炎和水痘带状疱疹病毒的MRNA疫苗的密码子优化基准相比，LinearDesign显著改善了mRNA半衰期和蛋白质表达，并使小鼠的抗体效价大幅提高高达128倍。这一结果揭示了原则性信使核糖核酸设计的巨大潜力，并使探索以前无法达到但高度稳定和高效的设计成为可能。我们的工作是疫苗和其他基于信使核糖核酸的药物编码治疗性蛋白的及时工具，如单抗和抗癌药物。一种基于计算语言学中建立的概念的算法可以快速原则性地设计mRNA疫苗，优化结构稳定性和密码子使用，从而改善半衰期、蛋白质表达和免疫反应。
Messenger RNA (mRNA) vaccines are being used to combat the spread of COVID-19 (refs. ), but they still exhibit critical limitations caused by mRNA instability and degradation, which are major obstacles for the storage, distribution and efficacy of the vaccine products. Increasing secondary structure lengthens mRNA half-life, which, together with optimal codons, improves protein expression. Therefore, a principled mRNA design algorithm must optimize both structural stability and codon usage. However, owing to synonymous codons, the mRNA design space is prohibitively large—for example, there are around 2.4 × 10632 candidate mRNA sequences for the SARS-CoV-2 spike protein. This poses insurmountable computational challenges. Here we provide a simple and unexpected solution using the classical concept of lattice parsing in computational linguistics, where finding the optimal mRNA sequence is analogous to identifying the most likely sentence among similar-sounding alternatives. Our algorithm LinearDesign finds an optimal mRNA design for the spike protein in just 11 minutes, and can concurrently optimize stability and codon usage. LinearDesign substantially improves mRNA half-life and protein expression, and profoundly increases antibody titre by up to 128 times in mice compared to the codon-optimization benchmark on mRNA vaccines for COVID-19 and varicella-zoster virus. This result reveals the great potential of principled mRNA design and enables the exploration of previously unreachable but highly stable and efficient designs. Our work is a timely tool for vaccines and other mRNA-based medicines encoding therapeutic proteins such as monoclonal antibodies and anti-cancer drugs. An algorithm based on concepts established in computational linguistics enables rapid principled design of mRNA vaccines optimizing both structural stability and codon usage, resulting in improved half-life, protein expression and immune responses.
登录
查看更多内容
影响因子：
16.6
作者：
Leppek, Kathrin;Byeon, Gun Woo;Das, Rhiju
通讯作者：
Das, Rhiju
影响因子：
12.4
作者：
Kariko, Katalin;Muramatsu, Hiromi;Welsh, Frank A.;Ludwig, Janos;Kato, Hiroki;Akira, Shizuo;Weissman, Drew
通讯作者：
Weissman, Drew
影响因子：
56.9
作者：
Liu, Lin;Botos, Istvan;Davies, David R.
通讯作者：
Davies, David R.
DOI：
10.1056/nejmoa2035389
发表时间：
2021-02-04
期刊：
The New England journal of medicine
影响因子：
--
作者：
Baden LR;El Sahly HM;Essink B;Kotloff K;Frey S;Novak R;Diemert D;Spector SA;Rouphael N;Creech CB;McGettigan J;Khetan S;Segall N;Solis J;Brosz A;Fierro C;Schwartz H;Neuzil K;Corey L;Gilbert P;Janes H;Follmann D;Marovich M;Mascola J;Polakowski L;Ledgerwood J;Graham BS;Bennett H;Pajon R;Knightly C;Leav B;Deng W;Zhou H;Han S;Ivarsson M;Miller J;Zaks T;COVE Study Group
通讯作者：
COVE Study Group
影响因子：
64.8
作者：
Gebre MS;Rauch S;Roth N;Yu J;Chandrashekar A;Mercado NB;He X;Liu J;McMahan K;Martinot A;Martinez DR;Giffin V;Hope D;Patel S;Sellers D;Sanborn O;Barrett J;Liu X;Cole AC;Pessaint L;Valentin D;Flinchbaugh Z;Yalley-Ogunro J;Muench J;Brown R;Cook A;Teow E;Andersen H;Lewis MG;Boon ACM;Baric RS;Mueller SO;Petsch B;Barouch DH
通讯作者：
Barouch DH