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

Abstract

The global pandemic of COVID-19 disease caused by infection with the SARS-CoV-2 coronavirus, has produce an urgent requirement and search for improved treatments whilst effective vaccines are developed. A strategy for improved drug therapy is to increase levels of endogenous reactive metabolites for selective toxicity to SARS-CoV-2 by preferential damage to the viral proteome. Key reactive metabolites producing major quantitative damage to the proteome in physiological systems are: reactive oxygen species (ROS) and the reactive glycating agent methylglyoxal (MG); cysteine residues and arginine residues are their most susceptible targets, respectively. From sequenced-based prediction of the SARS-CoV-2 proteome, we found 0.8-fold enrichment or depletion of cysteine residues in functional domains of the viral proteome; whereas there was a 4.6-fold enrichment of arginine residues, suggesting SARS-CoV-2 is resistant to oxidative agents and sensitive to MG. We examined activated arginine residues in functional domain with predicted low pKa by neighbouring group interaction in the SARS-CoV-2 We found 25 such arginine residues, including 2 in the spike protein and 10 in the nucleoprotein. These sites were partially conserved in related coronaviridae: SARS-COV and MERS. We also screened and identified drugs which increase cellular MG concentration to virucidal levels and found two antitumor drugs with historical antiviral activity, doxorubicin and paclitaxel were the best candidate for repurposing. Our findings provide evidence of potential vulnerability of SARS-CoV-2 to inactivation by MG and a scientific rationale for repurposing of doxorubicin and paclitaxel for treatment of COVID-19 disease, providing efficacy and adequate therapeutic index may be established