Vulnerabilities of the SARS-CoV-2 Virus to Proteotoxicity—Opportunity for Repurposed Chemotherapy of COVID-19 Infection
المؤلف | Al-Motawa, Maryam S. |
المؤلف | Abbas, Hafsa |
المؤلف | Wijten, Patrick |
المؤلف | de la Fuente, Alberto |
المؤلف | Xue, Mingzhan |
المؤلف | Rabbani, Naila |
المؤلف | Thornalley, Paul J. |
تاريخ الإتاحة | 2023-08-31T19:43:57Z |
تاريخ النشر | 2020-10-09 |
اسم المنشور | Frontiers in Pharmacology |
المعرّف | http://dx.doi.org/10.3389/fphar.2020.585408 |
الاقتباس | Al-Motawa, M. S., Abbas, H., Wijten, P., De la Fuente, A., Xue, M., Rabbani, N., & Thornalley, P. J. (2020). Vulnerabilities of the SARS-CoV-2 virus to proteotoxicity—opportunity for repurposed chemotherapy of COVID-19 infection. Frontiers in pharmacology, 11, 585408. |
الرقم المعياري الدولي للكتاب | 1663-9812 |
الملخص | 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 while 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 coronavirus predicted to be in functional domains, we examined which are activated toward modification by MG – residues with predicted or expected low pKa by neighboring 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. |
راعي المشروع | - Qatar Foundation - PhD studentship. - Qatar Foundation - (project code QB-14). - Qatar University - COVID-19 research (project code QU ERG-CMED-2020-1). |
اللغة | en |
الناشر | Frontiers Media |
الموضوع | bioinformatics coronavirus COVID-19 doxorubicin glyoxalase methylglyoxal paclitaxel proteomics |
النوع | Article |
رقم المجلد | 11 |
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