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Effective inhibition of MERS-CoV infection by resveratrol.

By consecutive administration of resveratrol, we were able to reduce the concentration of resveratrol while achieving inhibitory effectiveness against MERS-CoV. CONCLUSION: In this study, we first demonstrated that resveratrol is a potent anti-MERS agent in vitro …

Therapeutic blockade of inflammation in severe COVID-19 infection with intravenous N-acetylcysteine

Glucose 6-phosphate dehydrogenase (G6PD) deficiency facilitates human coronavirus infection due to glutathione depletion. G6PD deficiency may especially predispose to hemolysis upon coronavirus disease-2019 (COVID-19) infection when employing pro-oxidant therapy. However, glutathione depletion is reversible by N-acetylcysteine (NAC) administration. We describe a severe case of COVID-19 infection in a G6PD-deficient patient treated with hydroxychloroquine who benefited from intravenous (IV) NAC beyond reversal of hemolysis. NAC blocked hemolysis and elevation of liver enzymes, C-reactive protein (CRP), and ferritin and allowed removal from respirator and veno-venous extracorporeal membrane oxygenator and full recovery of the G6PD-deficient patient. NAC was also administered to 9 additional respirator-dependent COVID-19-infected patients without G6PD deficiency. NAC elicited clinical improvement and markedly reduced CRP in all patients and ferritin in 9/10 patients. NAC mechanism of action may involve the blockade of viral infection and the ensuing cytokine storm that warrant follow-up confirmatory studies in the setting of controlled clinical trials. Keywords: Coronavirus 19, COVID-19, N-acetylcysteine, Glutathione, Glucose 6-phosphate dehydrogenase, Mechanistic target of rapamycin, C-reactive protein, Ferritin, Respirator, Extracorporeal membrane oxygenation

Potential therapeutic effects of Resveratrol against SARS-CoV-2

Home Acta Virologica 2020 Acta Virologica Vol.64, No.3, p.276-280, 2020 --- Novel Coronavirus COVID-19 or Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as well as Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), are human pathogens. Current pandemics of SARS-CoV-2 represents a major health problem worldwide, with over four million cases and more than 300,000 deaths in the world. Development of effective therapy thus became an emergency. This report aims to highlight Resveratrol as possible therapeutic candidate in SARS-CoV-2 infection. The antiviral efficacy of Resveratrol was demonstrated for several viruses, including coronavirus. Resveratrol was shown to mitigate the major pathways involved in the pathogenesis of SARS-CoV-2, including regulation of the renin-angiotensin system (RAS) and expression of angiotensin-converting enzyme 2 (ACE2), stimulation of immune system and downregulation of pro-inflammatory cytokines release. It was also reported to promote SIRT1 and p53 signaling pathways and increase cytotoxic T lymphocytes (CTLs) and natural killer (NK) immune cells. In addition, Resveratrol was demonstrated to be a stimulator of fetal hemoglobin and a potent antioxidant, by trapping reactive oxygen species (ROS). According to these reports, Resveratrol could be proposed as potential therapeutics in the treatment of SARS-CoV-2. Keywords: SARS-CoV-2; Resveratrol; antiviral activity; immune response; ACE2; oxidative stress; HbF.

Medical journal article shows several key aspects of RESV and virus inhibition against another highly virulent virus in pigs.

Antiviral properties of resveratrol against pseudorabies virus are associated with the inhibition of IκB kinase activation. (Note, this study is not about COVID-19 directly, however its illustrative of how RESV can work to prevent and/or atetnuate a much more pathogenic virus that infects the brain in a way that is relevant to COVID-19, when we consider that RESV has similarly been shown to inhibit the SARS-CoV-2 virus (as well as MERS and SARS-CoV-1) in vitro, in the lab.

Stilbene-based natural compounds as promising drug candidates against COVID-19

Note that resveratrol is already available in the supply chain and inexpensive. J Biomol Struct Dyn . 2020 May 12;1-10. doi: 10.1080/07391102.2020.1762743. Online ahead of print. Hussain Mustatab Wahedi , Sajjad Ahmad , Sumra Wajid Abbasi PMID: 32345140 DOI: 10.1080/07391102.2020.1762743 The pandemic coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a great threat to public health. Currently, no potent medicine is available to treat COVID-19. Quest for new drugs especially from natural plant sources is an area of immense potential. The current study aimed to repurpose stilbenoid analogs, reported for some other biological activities, against SARS-CoV-2 spike protein and human ACE2 receptor complex for their affinity and stability using molecular dynamics simulation and binding free energy analysis based on molecular docking. Four compounds in total were probed for their binding affinity using molecular docking. All of the compounds showed good affinity (> -7 kcal/mol). However, fifty nanoseconds molecular dynamic simulation in aqueous solution revealed highly stable bound conformation of resveratrol to the viral protein: ACE2 receptor complex. Net free energy of binding using MM-PBSA also affirmed the stability of the resveratrol-protein complex. Based on the results, we report that stilbene based compounds in general and resveratrol, in particular, can be promising anti-COVID-19 drug candidates acting through disruption of the spike protein. Our findings in this study are promising and call for further in vitro and in vivo testing of stiblenoids, especially resveratrol against the COVID-19. Stilbenoid analogs could be potential disruptors of SARS-CoV-2 spike protein and human ACE2 receptor complex.In particular, resveratrol revealed highly stable conformation to the viral protein: ACE2 receptor complex.The strong interaction of resveratrol is affirmed by molecular dynamic simulation studies and better net free energies. Keywords: COVID-19; MM-PBSA; Stilbenoids; molecular docking; molecular dynamic simulations

Resveratrol inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) in cultured Vero cells

Phytotherapy Research/Early View OPEN ACCESS Dear Editor, An emergence of the novel coronavirus designated as the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) at the end of 2019 has triggered an ongoing pandemic of coronavirus disease 2019 (COVID‐19) globally. As of 22nd September 2020, more than 30,949,804 confirmed cases and 959,116 deaths have been reported worldwide (WHO, 2020). COVID‐19 bears several pathological hallmarks including fever, breathing difficulty, bilateral lung infiltration, and death in the most extreme cases (Huang et al., 2020). Several anti‐viral drugs have been used to target the SARS‐CoV‐2 infection. These drugs include remdesivir, ribavirin, penciclovir, lopinavir/ritonavir, chloroquine (Wang, Cao, et al., 2020). However, most of these medicines have limited efficacy to reduce the severity and, particularly the mortality of COVID‐19 patients. In addition, some of them have serious side effects (Cao et al., 2020; Wang, Zhang, et al., 2020). The shortcomings of current medicines lead scientists and physicians to continuously look up for better remedies for COVID‐19. Resveratrol is a promising one of those remedies. Resveratrol (3,4,5‐trihydroxy‐trans‐stilbene, RES) is a phenolic compound produced by various members of spermatophytes such as grapes, mulberry, and peanuts. It displays potential effects to suppress replication of several viruses including dengue virus (DENV), Zika virus (ZIKV), as well as influenza virus (Mohd, Zainal, Tan, & Sazaly, 2019; Paemanee, Hitakarun, Roytrakul, & Duncan, 2018). Particularly, RES has the capacity to significantly inhibit MERS‐CoV infection and increases the viability of cells infected by this virus (Lin et al., 2017). Based on these observations, we have initiated a study to test whether RES also inhibits the replication of SARS‐CoV‐2. This study has been approved by the ethics committees from Shenzhen Third People's Hospital and strictly follows the approved protocol. All procedures involving SARS‐CoV‐2 infection were performed in a biosafety level 3 laboratory. First of all, the dose‐responsive study of RES (from 1.56 to 200 μM) was performed to assess whether RES exhibits cytotoxicity on Vero cells (ATCC, CCL‐81). The results showed that cell viability of Vero cells remained above 90 and 80% with the RES at concentrations of 100 and 200 μM for 48 hr, respectively (Figure 1a). The results suggested that RES had little cytotoxicity to Vero cells even at such high concentrations which is consistent with previous reports on various other cell types including oocytes or embryos (Li et al., 2016). To test the effects of RES on SARS‐CoV‐2 replication, the Vero cells were infected with SARS‐CoV‐2 (BetaCoV/Shenzhen/SZTH‐003/2020 strain virus GISAID access number: EPI_ISL_406594) at a multiplicity of infection (MOI) of 0.01 and treated with different concentrations of RES. The viral replication was analyzed at 48 hr postinfection with quantitative reverse transcription polymerase chain reaction (qRT‐PCR) and immunofluorescence assay (Figure 1b,c). The results showed that RES significantly inhibited the replication of SARS‐CoV‐2 with an EC50 (half‐maximal effective concentration) of 4.48 μM. To examine the time window of RES on SARS‐CoV‐2 infection, RES was incubated with cells before and/or after their infection and the time‐of‐addition assay was used to evaluate the effects described by Wang, Cao, et al. (2020). Briefly, viral RNA was extracted from the harvested supernatants and then qRT‐PCR was performed. The SARS‐CoV‐2 mRNA copy number was compared between the mock‐treated and RES‐treated cells. The results showed that the inhibitory rate for SARS‐CoV‐2 replication in cells pre‐treated with RES 50 μM for 2 hr was less than 20%; however, inhibitory rate in cells treated with RES after virus infection was excessive at 98% which was similar to the full time treatment (pre and after treatment together). The results indicate that the inhibitory effects of RES on SARS‐CoV‐2 replication have a strong presence after the viruses are inoculated into the culture medium. It has been reported that RES possesses highly stable conformation to the viral S protein‐ACE2 receptor complex (Wahedi, Ahmad, & Abbasi, 2020). Interestingly, when cells were co‐incubated with virus and RES for 1 hr and then the RES was removed for additional 48 hr incubation, the inhibitory rate was still at around 64% (Figure 1d). This suggests that RES has a blocking capacity to the viral entry into cells. These novel data support the potential utility of RES on SARS‐CoV‐2 infection.