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Vulnerabilities of the SARS-CoV-2 Virus to Proteotoxicity — Opportunity for Repurposed Chemotherapy of COVID-19 Infection

44 Pages Posted: 5 May 2020 Publication Status: Review Complete

See all articles by Maryam Al-Motawa

Maryam Al-Motawa

Hamad Bin Khalifa University - Diabetes Research Center

Hafsa Abbas

University of Warwick - Clinical Sciences Research Laboratories

Patrick Wijten

Hamad Bin Khalifa University - Diabetes Research Center

Alberto de la Fuente

Hamad Bin Khalifa University - Diabetes Research Center

Mingzhan Xue

Hamad Bin Khalifa University - Diabetes Research Center

Naila Rabbani

University of Warwick - Clinical Sciences Research Laboratories

Paul Thornalley

Hamad Bin Khalifa University - Diabetes Research Center

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Abstract

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.

Funding: Qatar Foundation and Qatar University.

Conflict of Interest: The authors declare no competing interests.

Keywords: SARS-CoV-2, COVID-19, coronaviridae, protein informatics, Methylglyoxal, glyoxalase, doxorubicin, paclitaxel

Suggested Citation

Al-Motawa, Maryam and Abbas, Hafsa and Wijten, Patrick and Fuente, Alberto de la and Xue, Mingzhan and Rabbani, Naila and Thornalley, Paul, Vulnerabilities of the SARS-CoV-2 Virus to Proteotoxicity — Opportunity for Repurposed Chemotherapy of COVID-19 Infection. Available at SSRN: https://ssrn.com/abstract=3582068 or http://dx.doi.org/10.2139/ssrn.3582068
This version of the paper has not been formally peer reviewed.

Maryam Al-Motawa

Hamad Bin Khalifa University - Diabetes Research Center ( email )

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Hafsa Abbas

University of Warwick - Clinical Sciences Research Laboratories ( email )

United Kingdom

Patrick Wijten

Hamad Bin Khalifa University - Diabetes Research Center ( email )

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Alberto de la Fuente

Hamad Bin Khalifa University - Diabetes Research Center

Qatar

Mingzhan Xue

Hamad Bin Khalifa University - Diabetes Research Center ( email )

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Naila Rabbani

University of Warwick - Clinical Sciences Research Laboratories ( email )

United Kingdom

Paul Thornalley (Contact Author)

Hamad Bin Khalifa University - Diabetes Research Center ( email )

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