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

The global pandemic of COVID-19 disease caused by infection with the SARS-CoV-2 coronavirus, has produced 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. For arginine residues of the SARS-CoV-2 predicted to be in functional domains, we examined which are activated towards modification by MG - residues with predicted or expected low pKa by neighbouring group in interactions. 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. Finally, we identified drugs which increase cellular MG concentration to virucidal levels: antitumor drugs with historical antiviral activity, doxorubicin and paclitaxel. 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.

C_3 POLYMORPHISM IN CHINESE POPULATION IN SHAANXI / 西安交通大学学报(医学版)

273 chinese have been studied with high voltage electrophoresis and immumofixation to survey the polymorphism of the third component of human complement in Shaanxi Provice Two C_3 phenotypes were found in this population, they are C_3SS and C_3FS The frequencies of C_3SS and C_3FS are 98.53% and 1.47% respectively. The frequency of C_3S gene is 0.9926 and C_3F gene 0.0073. These results are similar to other studies in China and this group was in Hardy-Weinberg equilibrium. Compared with Negro and Caucasian, the chinese population in Shaanxi Province has a significant difference in C_3 polymorphism.