Vulnerabilities of the SARS-CoV-2 virus to proteotoxicity — opportunity for repurposed chemotherapy of COVID-19 infection

There is an urgent requirement for improved treatments of COVID-19 disease. A strategy for chemotherapy is to increase levels of endogenous reactive metabolites — such as reactive oxygen species and arginine-directed glycating agent, methylglyoxal — for selective toxicity to SARS-CoV-2. Sequence analysis of functional domains in the SARS-CoV-2 proteome showed 0.8 fold depletion of cysteine residues and 4.9 fold enrichment of arginine residues, suggesting methylglyoxal modification may inactivate the virus. We discovered the peptide motif for MG modification: 3 – 5-fold enrichment of cationic residues preceding the target arginine. There was 5-fold enrichment of methylglyoxal modification sites in the SARS-CoV-2 proteome, compared to the human host - indicating selective toxicity of methylglyoxal to the virus. We found antitumor drugs, doxorubicin and paclitaxel, increase cellular methylglyoxal to virucidal levels. Taken together, these findings reveal a proteomic vulnerability of SARS-CoV-2 to methylglyoxal modification and provide a rationale for repurposing doxorubicin and paclitaxel for COVID-19 treatment.