key: cord-1051084-1s8t6vib
authors: Nadhan, Revathy; Patra, Dipyaman; Krishnan, Neethu; Rajan, Arathi; Gopala, Srinivas; Ravi, Dashnamoorthy; Srinivas, Priya
title: Perspectives on mechanistic implications of ROS inducers for targeting viral infections
date: 2020-10-14
journal: Eur J Pharmacol
DOI: 10.1016/j.ejphar.2020.173621
sha: 8ad8c93e3478f595becab1790ac05687db2b9cd2
doc_id: 1051084
cord_uid: 1s8t6vib

In this perspective, we propose to leverage reactive oxygen species (ROS) induction as a potential therapeutic measure against viral infections. Our rationale for targeting RNA viral infections by pro-oxidants is routed on the mechanistic hypothesis that ROS based treatment paradigm could impair RNA integrity faster than the other macromolecules. Though antiviral drugs with antioxidant properties confer potential abilities for preventing viral entry, those with pro-oxidant properties could induce the degradation of nascent viral RNA within the host cells, as RNAs are highly prone to ROS mediated degradation than DNA/proteins. We have previously established that Plumbagin is a highly potent ROS inducer, which acts through shifting of the host redox potential. Besides, it has been reported that Plumbagin treatment has the potential for interrupting viral RNA replication within the host cells. Since the on-going Corona Virus Disease - 2019 (COVID-19) global pandemic mediated by Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2) exhibits high infectivity, the development of appropriate antiviral therapeutic strategies remains to be an urgent unmet race against time. Therefore, additional experimental validation is warranted to determine the appropriateness of repurposable drug candidates, possibly ROS inducers, for fighting the pandemic which could lead to saving many lives from being lost to COVID-19.

. Thus, tipping oxidant-1 antioxidant balance using pharmacological agents towards antioxidant state should promote 2 viral replication and if shifted toward pro-oxidant state should result in enhanced oxidative 3 stress and inhibition of the viral replication (Chen et al., 2020a; Lee, 2018b; Nakamura et al., 4 2010). Hence, the administration of antioxidants like Vitamin C, which has been proved to be 5 preventive against viral pneumonia, can serve as an ideal prevention strategy against viral 6 infections; however, ROS induction can be superlative in disease therapy (Hemilä and 7 Louhiala, 2013; Kim et al., 2013) . Further, there are several host redox and other associated 8 genes which are modulated during a viral infection enabling the viral propagation and 9 pathogenesis as depicted in Table 1 ((Ahmed and Rahman, 2006; Bender and Hildt, 2019; 10 Bottino- Rojas et al., 2018; Checconi et al., 2020; Chen et al., 2020a; Cuadrado et al., 2020; 11 Jacoby and Choi, 1994; Lee, 2018a; Simenauer et al., 2019; Zhang et al., 2020) . 12 During a viral infection, as viral entry into the host cells is a continuous process, there arises 13 a question of selecting the suitable redox modulated antiviral strategy, i.e. whether to use the 14 ROS scavengers to prevent the viral entry into each of the host cells or to employ the pro-15 oxidants to target the viral RNA degradation. Though this decision stands imperative, it is 16 indeed dependent on the extent of viral infection in the patients. However, there appears a 17 concern about whether the ROS induction would affect the normal cells. Since the normal 18 cells have a stable redox homeostatic system as well as efficient machinery to repair the 19 nucleic acid damages resultant of ROS induction, they would strategically strive the 20 detrimental mechanistic effects of ROS. Conversely, the viral infected cells, which would 21 already have a viral-induced oxidative stress as well as compromised repair system (owing to 22 the viral evasion of the host repair systems) to overcome these detrimental nucleic acid 23 damages, would succumb to ROS induced cytotoxicity and resultant cell death owing to the mechanisms, the prominent of which is the NRF-2 mediated ones. However, this is a failed 1 defense system in cases of high viral titres in the infected cells, while this defense system 2 remains active in the normal cells. Thus, NRF-2 mediated antioxidant mechanism additively 3 acts in preventing the damaging cellular effects owing to ROS induction in the 4 normal/infection-resistant cells, while the failed NRF-2 system in viral infected cells 5 wouldn't interfere with the ROS induced damages, which adds up with viral-induced 6 oxidative stress to selectively target these viral infected cells. The aforesaid properties 7 substantiate the leverage of ROS inducers than the ROS scavengers as a suitable anti-viral 8 therapeutic strategy. Therefore, the pro-oxidants possess the ability to selectively induce 9 enhanced lethal oxidative damages in RNA than that could be induced in the DNA, thus 10 stalling the translation process, which sufficiently and satisfactorily calls for proposals in 11 employing ROS inducers as lead molecules for the viral RNA infection treatment, including 12 SARS-CoV-2 (Figure 1) .

Quinones, in general, are strong ROS inducers; however, among structurally similar 15 quinones, Plumbagin is not only an excellent ROS inducer but also has a higher ability to 16 alter the redox potential which is mechanistically responsible for antiviral, antimicrobial, DiGuiseppi and Fridovich, 1982; Farr et al., 1985; Hassan and Fridovich, 1979) . Moreover, Plumbagin is absolutely necessary, prior to evaluation for COVID-19 targeted therapy. 

low levels of oxidative stress in the host cells. • Strong ROS inducers would be damaging RNA, at lower concentrations, than DNA. • Plumbagin is a potent ROS inducer

• Plumbagin could be used for SARS-CoV-2 therapy