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.
