RAPID: Developing a universal modular platform to engineer coronavirus vaccine candidates

获得该奖项后，化学部的生命过程化学项目支持了伊利诺伊大学香槟分校Angad Mehta博士的研究，该研究旨在制造需要非天然化合物才能繁殖的严重急性呼吸综合征冠状病毒2(SARS-CoV-2)的活减毒形式。SARS-CoV-2是导致2019年冠状病毒病的病毒(新冠肺炎)。减毒活病毒降低了致病能力，但仍能为人类提供免疫力。因此，减毒活病毒是开发针对广泛传播的病毒感染的疫苗的有效策略之一。病毒的基因组核糖核酸必须经过甲基修饰才能被感染的细胞复制，而这个甲基是通过使用天然化合物S-腺苷蛋氨酸(ADOMet)的酶来添加的。梅塔博士的项目为这一关键的甲基化步骤设计了SARS-CoV-2粒子，这些粒子使用合成形式的ADOMet(称为xADOMet)。由此产生的经过改造的SARS-CoV-2*是实验室中的活病毒，在实验室中可以添加xADOMet作为必要的补充。然而，SARS-CoV-2*不能在正常细胞中复制，因为在正常细胞中不存在xAdobe Met，但仍然可以在感染患者中产生免疫反应。对社会的影响是，为开发疫苗而设计了一个独特的平台，以应对病毒性疾病，包括新冠肺炎大流行。这个项目的更广泛的影响包括对研究生的强大的跨学科培训。这项研究的目标是开发活的减毒SARS-CoV-2粒子，这种粒子依赖于其复制所必需的辅因子的非自然版本，该辅因子在实验室环境中添加，但在受感染的宿主中不可用。SARS-CoV-2病毒需要S-腺苷蛋氨酸(ADOMet)作为辅因子，通过甲基转移酶对病毒RNA进行关键的甲基化，以翻译其基因并复制其基因组。通过这个项目，设计出了一种冠状病毒株(SARS-CoV-2*)，它利用并依赖于一种非天然的ADOMet类似物(XADOMet)进行关键的甲基化反应。这种病毒需要在实验室中补充xADOMet才能复制。一旦注射到宿主体内，这种病毒株就可以感染细胞，并可能在宿主体内引发免疫反应，但在没有外源补充xAdobe Met的情况下无法复制。其目标是合成一系列xADOMet化合物；使用xADOMet化合物通过定向进化来设计SARS-CoV-2*；并测试减毒活病毒在细胞培养中诱导免疫反应。ADOMet依赖甲基化机制在所有已知的冠状病毒病原体中都是保守的，因此有可能成为远远超出SARS-CoV-2的疫苗开发的深远和模块化平台。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

With this award, the Chemistry of Life Processes program in the Chemistry Division supports the studies by Dr. Angad Mehta at the University of Illinois at Urbana-Champaign to make live attenuated forms of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that require an unnatural compound to reproduce. SARS-CoV-2 is the virus that causes coronavirus disease 2019 (COVID-19). Live-attenuated viruses have reduced abilities to cause disease, but remain capable of providing immunity in humans. As such, live-attenuated viruses represent one of the effective strategies for the development of vaccines against wide-spread viral infections. The genomic RNA of the virus must be modified with a methyl group in order to be copied by infected cells, and this methyl group is added by enzymes using the natural compound S-adenosylmethionine (AdoMet). Dr. Mehta’s project engineers SARS-CoV-2 particles that use synthetic forms of AdoMet (called xAdoMet) for this critical methylation step. The resulting engineered SARS-CoV-2* is a live virus in a laboratory, where xAdoMet can be added as a required supplement. The SARS-CoV-2*, however, cannot reproduce in normal cells, where xAdoMet is not present, but can still result in an immune response in an infected patient. The impact on society is that a unique platform is engineered for the development of vaccines to address viral diseases, including the COVID-19 pandemic. The broader impacts of this project include the strong cross-disciplinary training of graduate students.This goal of this study is to develop live attenuated SARS-CoV-2 particles that are dependent on an unnatural version of an essential cofactor for its replication that is added in a laboratory setting, but not available in the infected host. SARS-CoV-2 requires S-adenosylmethionine (AdoMet) as a cofactor for a critical methylation of the viral RNA by a methyl transferase in order to translate its genes and replicate its genome. Through this project, a strain of the coronavirus (SARS-CoV-2*) is engineered that utilizes and is dependent on an unnatural analogue of AdoMet (xAdoMet) for the critical methylation reactions. Such a virus requires supplements of xAdoMet in a laboratory in order to replicate. Once injected into a host, this viral strain can infect a cell and potentially induce an immune response in the host, but cannot replicate in the absence of exogenous supplementation with xAdoMet. The objectives are to synthesize a series of xAdoMet compounds; use the xAdoMet compounds to engineer SARS-CoV-2* through directed evolution; and test the live attenuated virus for induction of immune response in cell culture. The AdoMet-dependent methylation mechanism is conserved in all known coronavirus pathogens and, therefore, has the potential to serve as a far-reaching and modular platform for vaccine development well beyond SARS-CoV-2.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.