In Silico Screen and 19F Nuclear Magnetic Resonance Spectroscopy Enabled Chemical Synthesis of a Library of Carmofur Analogs as Potential Inhibitors of the SARS-CoV-2 Main Protease (Mpro)

Xina Wang, Julia Vu, and Edward Njoo

Aspiring Scholars Research Directed Program


Carmofur, a 5-fluorouracil derivative, was initially developed as an antineoplastic agent that inhibits acid ceramidase and tested for its efficacy on colorectal cancer cell lines. More recently, through drug repurposing efforts, it has been identified as a covalent inhibitor of the main protease of SARS-CoV-2. This SARS-CoV-2 main protease (Mpro) plays an essential role in the processing of the polyproteins that are translated from the viral RNA, therefore making it an attractive drug target for the treatment of COVID-19.. Here, we present the in silico evaluation and synthesis of carmofur and a library of related 5-fluorouracil analogs with aliphatic, amino acid, and aromatic fragments against mutations in Mpro. Homology modeling was used to determine the interactions between carmofur analogs and Mpro as a result of the mutations and their effects on the binding affinity of our analogs, revealing potential hit compounds to further develop for combating COVID-19. Furthermore, using the 5-fluorinated position as a handle, benchtop 19F nuclear magnetic resonance spectroscopy (NMR) has enabled the real-time quantitative monitoring and scalable synthesis of novel 5-fluorouracil analogs as potentially more effective inhibitors. Further studies include biological assaying towards the evaluation of our analogs against Mpro and human colorectal carcinoma cell lines.

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