Apr 9, 2020

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

BioRxiv : the Preprint Server for Biology
M. Al-MotawaPaul Thornalley


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.

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