Antiviral Activity of Glyoxals

Bock, Cheryl A.; Brug, J.; Walop, J. N.

doi:10.1038/179706a0

Cited by 25 publications

(7 citation statements)

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“…Antiviral activity of supraphysiological concentrations of MG was reported historically ( De Bock et al., 1957 ). More recently, inhibition of cytopathic effect of strains of influenza B by MG was investigated.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2020

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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 pK a 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, w e 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.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2020

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“…We recently proposed an evaluation of BBGD for antiviral activity against SARS-CoV-2 [ 120 ]. Antiviral activity of supraphysiological concentrations of MG was reported historically [ 121 ], with inhibition of the cytopathic effect of influenza B strains by MG where the most sensitive strain gave a median inhibitory concentration of 23 ± 7 µM MG [ 122 ]. We explored the SARS-CoV-2 proteome for the enrichment of arginine residues—the major target of MG modification—in functional domains.…”

Section: Other Potential Therapeutic Applications and Experimental Ap...mentioning

confidence: 99%

Emerging Glycation-Based Therapeutics—Glyoxalase 1 Inducers and Glyoxalase 1 Inhibitors

Rabbani

Thornalley

2022

IJMS

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The abnormal accumulation of methylglyoxal (MG) leading to increased glycation of protein and DNA has emerged as an important metabolic stress, dicarbonyl stress, linked to aging, and disease. Increased MG glycation produces inactivation and misfolding of proteins, cell dysfunction, activation of the unfolded protein response, and related low-grade inflammation. Glycation of DNA and the spliceosome contribute to an antiproliferative and apoptotic response of high, cytotoxic levels of MG. Glyoxalase 1 (Glo1) of the glyoxalase system has a major role in the metabolism of MG. Small molecule inducers of Glo1, Glo1 inducers, have been developed to alleviate dicarbonyl stress as a prospective treatment for the prevention and early-stage reversal of type 2 diabetes and prevention of vascular complications of diabetes. The first clinical trial with the Glo1 inducer, trans-resveratrol and hesperetin combination (tRES-HESP)—a randomized, double-blind, placebo-controlled crossover phase 2A study for correction of insulin resistance in overweight and obese subjects, was completed successfully. tRES-HESP corrected insulin resistance, improved dysglycemia, and low-grade inflammation. Cell permeable Glo1 inhibitor prodrugs have been developed to induce severe dicarbonyl stress as a prospective treatment for cancer—particularly for high Glo1 expressing-related multidrug-resistant tumors. The prototype Glo1 inhibitor is prodrug S-p-bromobenzylglutathione cyclopentyl diester (BBGD). It has antitumor activity in vitro and in tumor-bearing mice in vivo. In the National Cancer Institute human tumor cell line screen, BBGD was most active against the glioblastoma SNB-19 cell line. Recently, potent antitumor activity was found in glioblastoma multiforme tumor-bearing mice. High Glo1 expression is a negative survival factor in chemotherapy of breast cancer where adjunct therapy with a Glo1 inhibitor may improve treatment outcomes. BBGD has not yet been evaluated clinically. Glycation by MG now appears to be a pathogenic process that may be pharmacologically manipulated for therapeutic outcomes of potentially important clinical impact.

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“…Antiviral activity of supraphysiological concentrations of MG was reported historically (De Bock et al, 1957). More recently, inhibition of cytopathic effect of strains of influenza B by MG was investigated.…”

Section: Pharmacological Increase Of Cellular Methylglyoxal To Virucimentioning

confidence: 99%

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

Al-Motawa

Abbas

Wijten

et al. 2020

Preprint

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bioRxiv preprint which are glycated to hydroimidazolone MG-H1 with loss of charge, all related electrostatic interactions and, typically, resistance to proteolytic cleavage close to the site of modification ( Figure 1B) (Rabbani et al., 2016b).Key to exploring if reactive metabolites of the host may be exploited to produce a virucidal response against SARS-CoV-2 is to identify proteomic vulnerabilities of the virus.Currently it is unknown if target amino acid residues of reactive metabolites are enriched in functional domains of the viral proteome, and if these targets are enriched in the viral proteome, compared to the human host. It also unknown if there are investigational new drugs or current clinically approved drugs that increase reactive metabolites to virucidal levels in the cellular environment where SARS-CoV-2 undergo cell fusion and propagation.To address this knowledge gap, we initiated a series of studies using protein informatics tools, available proteomics data and a cell model used in SARS-CoV-2 fusion and propagation. Herein we report the susceptibility of the SARS-CoV-2 virus to increased MG or "dicarbonyl stress" (Rabbani et al., 2016b) based on enrichment of arginine residues in functional domains and enrichment of amino acid motif MG modification sites in the SARS-CoV-2 proteome, and two clinically approved antitumor drugs that increase the cellular concentration of MG to virucidal levels. We propose these drugs be considered for repurposing for treatment of COVID-19 disease. RESULTS Enrichment of arginine residues in the functional domains in the SARS-CoV-2 proteome.We acquired the reference sequences of the 29 proteins of the SARS-CoV-2 proteome (Table S1) and also, for reference, 18,821 reviewed protein sequences of human host proteins from was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

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Antiviral Activity of Glyoxals

Cited by 25 publications

References 0 publications

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

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

Emerging Glycation-Based Therapeutics—Glyoxalase 1 Inducers and Glyoxalase 1 Inhibitors

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

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