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Further animal evaluations and clinical trials to develop appropriate methods to prevent the gradual degradation of disulfiram in digestive processes/inner circulation and allow its transport to infected tissues is recommended if its potential anti-2019-nCoV activity via TOS II w...

Targeted Oxidation Strategy (TOS) for Potential Inhibition of Coronaviruses by Disulfiram — a 70-Year Old Anti- Alcoholism Drug

ChemRxiv, (2020)

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Abstract

In the new millennium, the outbreak of new coronavirus has happened three times: SARS-CoV, MERS-CoV, and 2019-nCoV Unfortunately, we still have no pharmaceutical weapons against the diseases caused by these viruses The pandemic of 2019-nCoV reminds us of the urgency to search new drugs with totally different mechanism that may target th...More

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Introduction
  • Aggressive RNA viruses are typically characterized by rapid reproductive activities in cytoplasm.
  • Disulfide reduction to thiol/thiolate (DRT) by GSH in local cytosolic microenvironments with high GSH:GSSG ratios can restore the primitive active form of proteins even if aberrant TOD occurs occasionally
  • The authors postulated that such combination of OQ and DRT may likely be an essential reductive-protection mechanism evolved by aerobic organisms to reconcile the conflicting vital needs of both oxygen and oxidatively-unstable intracellular functional sites as a response to the transition from an O2-lean atmosphere to an O2-rich one on ancient Earth.
  • How to overcome OQ/DRT on demand represents a key challenge for potential therapeutic applications of TOD, such as killing malignant cells and inhibiting cytosolic proliferation of RNA viruses in vivo
Highlights
  • Aggressive RNA viruses are typically characterized by rapid reproductive activities in cytoplasm
  • How to overcome Oxidant quenching/disulfide reduction to thiol/thiolate on demand represents a key challenge for potential therapeutic applications of to disulfide, such as killing malignant cells and inhibiting cytosolic proliferation of RNA viruses in vivo
  • Type-I disulfide oxidants correspond to the situation where reaction 1 is both kinetically and thermodynamically more favorable than reaction 2, while type-II disulfide oxidants show complete reverse kinetic and thermodynamic behaviors
  • The encouraging cell-level anti-2019-nCoV activities of both disulfiram and PX-12 suggest the potential of using TOS II in inhibition of coronaviruses
  • Further animal evaluations and clinical trials to develop appropriate methods to prevent the gradual degradation of disulfiram in digestive processes/inner circulation and allow its transport to infected tissues is recommended if its potential anti-2019-nCoV activity via TOS II would be leveraged to a large extent
  • In addition to potential interference of cytosolic proliferations of coronaviruses, TOS II might be envisioned to trigger other significant physiological consequences such as inhibiting protein ubiquitinations via oxidation of the active cysteinyl thiols of ubiquitin-activating enzyme E1 and ubiquitin-conjugating enzyme E2 to form stable disulfides that can resist the reductive environments in cells
Results
  • Results and Discussion

    Chemical Principles Underlying TOS II and Potential Involvement of TOS II in Inhibition of 2019-nCoV The authors first reasoned that there should be four distinctive types of disulfide oxidants with characteristic kinetic and thermodynamic behaviors in two competitive intracellular TOD/DRT reactions: 1) reduction of the disulfide oxidant by GSH to form a new small-molecule disulfide; and 2) reduction of the disulfide oxidant by protein thiol to form targeted protein disulfide (Fig. 2A).
  • Type-I disulfide oxidants correspond to the situation where reaction 1 is both kinetically and thermodynamically more favorable than reaction 2, while type-II disulfide oxidants show complete reverse kinetic and thermodynamic behaviors.
  • For type-III disulfide oxidants, reaction 1 is kinetically more favorable than reaction 2, the opposite is true thermodynamically.
  • In contrast to type III, vice versa is true for type IV.
  • Types II and III should be more suitable for TOS II than types the author ands IV in cytosolic microenvironments with high ratios of GSH:GSSG.
  • Type III may be less desirable than type II due to kinetics
Conclusion
  • The authors have described the fundamental principles to overcome the intracellular reductive-protection mechanism for potential therapeutic purposes via TOS II.
  • The encouraging cell-level anti-2019-nCoV activities of both disulfiram and PX-12 suggest the potential of using TOS II in inhibition of coronaviruses.
  • In addition to potential interference of cytosolic proliferations of coronaviruses, TOS II might be envisioned to trigger other significant physiological consequences such as inhibiting protein ubiquitinations via oxidation of the active cysteinyl thiols of ubiquitin-activating enzyme E1 and ubiquitin-conjugating enzyme E2 to form stable disulfides that can resist the reductive environments in cells.
  • Considering the ubiquity of thiol/zinc-thiolate sites in proteins and their important biological roles, the authors hope that more research attention can be devoted to the development of TOS II drugs for various therapeutic applications
Tables
  • Table1: Cysteine(s) in zinc fingers, active sites or disulfide bonds in proteins of
  • Table2: Calculated non-covalent interaction energies in various media (corrected with BSSE, unit kcal·mol-1)
  • Table3: Selected top ranked docking results of Mpro
  • Table4: Selected top ranked docking results of PLpro
Download tables as Excel
Funding
  • Stills have no pharmaceutical weapons against the diseases caused by these viruses
  • Molecular docking against the two thiol proteases Mpro and PLpro of 2019-nCoV provide evidence to support a TOS II mechanism for two experimentally identified anti-2019-nCoV disulfide oxidants: disulfiram and PX-12
  • Disulfiram is an anti-alcoholism drug approved by FDA 70 years ago, it can be immediately used in phase III clinical trial for anti-2019-nCoV treatment
  • Aggressive RNA viruses are typically characterized by rapid reproductive activities in cytoplasm
  • Schematics illustrating the principle for target oxidation strategy : A
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Author
Luyan Xu
Luyan Xu
Jiahui Tong
Jiahui Tong
Yiran Wu
Yiran Wu
Suwen Zhao
Suwen Zhao
Bo-Lin Lin
Bo-Lin Lin
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