Part2: Flavonoids As Promising Antiviral Agents Against SARS-CoV-2 Infection: A Mechanistic Review
Mar 30, 2022
For more info. contact tina.xiang@wecistanche.com
3. Discussion
Flavonoids as a class of safe and abundant phytoconstituents have attracted a lot of attention regarding their beneficial effects on COVID-19, and several attempts have been made to assess the structure-activity relationship of these compounds against SARS-CoV-2 proteins [115,116]. This paper reviewed the potential antiviral mechanisms of flavonoids based on the in vitro and in vivo studies on different viruses that follow the same pathogenic mechanisms as SARS-CoV-2, including HIV, influenza virus, ebola virus, SARS, and MERS. Available data on all virus and host targets were included in this study. Figures 1 and 2 provide an overview of the direct and indirect mechanisms of flavonoids.
Click here to learn more products
Amongst direct antiviral mechanisms, inhibition of viral proteases is the most frequently reported property of flavonoids. Due to the high similarity of SARS-CoV-2 pro-teases to those of SARS, flavonoids with inhibitory effects on these enzymes, such as isoliquiritigenin, kaempferol, and its derivatives, quercetin and its derivatives, theaflavins, flavonoids derived from Angelica keiskei(Miq.) Koidz. and Broussonetia papyrifera(L.)L'Her.ex Vent. can be considered as candidates for future antiviral assessments against SARS-CoV-2 (Table 1). On the other hand, modulation of inflammatory host responses to viral infections by the flavonoids seems to be the most important mechanism by which the complications of viral infection are managed. Baicalin and baicalein, biochanin A, cirsimaritin, gallocatechin-7-gallate, and hesperidin are flavonoids with modulating effects on both TNF-α and ILs and thus, can regulate severe conditions due to malfunction of host immune system such as cytokine storm.
According to the current literature, theaflavins, quercetin, luteolin, myricetin, kaempferol, catechins, hesperidin, and baicalin were the most promising flavonoids against the aforementioned viruses. Regarding the herbal sources of flavonoids, the most studied plants were Camellia sinensis (L.)Kuntze (tea) and Scutellaria baicalensis Georgi (skullcap). Green tea is a rich source of catechins, whereas black tea mostly contains theaflavins. Flavonoids from both types of tea have shown direct antiviral properties. Since tea is a popular drink in the human diet, it can be suggested as a safe dietary intervention for COVID-19 patients with mild to moderate symptoms. Due to its acceptable safety profile, tea can also be introduced as a suitable candidate for investigation in future clinical trials. Skullcap is a medicinal plant mostly used in Chinese medicine and is the natural source of baicalin, baicalein, pyroxylin A, and wogonin. These flavonoids have demonstrated significant effects on the immune response of infected cells and animals via modulation of IFNs, endogenous antioxidant defense mechanisms, and inflammatory responses, as well as direct antiviral properties.
Some of the flavonoids reviewed in this study, such as cirsimaritin were shown to have antiviral activity higher than standard chemically synthesized drugs like ribavirin [59]. It should be mentioned that the results of in vitro antiviral studies do not necessarily guarantee the same potency and efficacy in clinical settings; though, they can be considered as a screening method to select the most effective compounds amongst numerous candidates for further in vivo and mechanistic evaluations. As previously mentioned, oseltamivir which is an anti-influenza agent has been designed and synthesized using shikimic acid, a plant-derived compound; thus, the introduced flavonoids in this review can be used as molecular backbones for the design and development of novel semisynthetic medicines with better bioavailability and clinical efficacy.
Despite hundreds of flavonoids evaluated against SARS-CoV-2 through virtual screen-ings, the experimental evidence on the in vitro or in vivo antiviral effect of these compounds against this exact type of virus is limited. Amongst the included flavonoids in our review, only four compounds, including baicalin, baicalein, quercetin, and isorhamnetin, were experimentally assessed in SARS-CoV-2-infected cells or animals.
Previous in silico studies and molecular analysis of different CoVs showed the potential antiviral effects of phytochemicals at different stages of viral biogenesis, including binding to ACE2, surface gangliosides, RdRp, viral spike protein, and viral protease in host cells, and paved the way for more clinical and experimental studies [9,117-123]. Nevertheless, it should be considered that an acceptable antiviral activity in virtual screenings does not necessarily guarantee in vivo antiviral activity, and that is why an overview of flavonoids with antiviral properties in experimental studies is a further step toward the selection of natural antiviral agents. On the other hand, several of the mechanisms suggested for antiviral flavonoids in virtual screenings are not vet experimentally evaluated. In vitro and in vivo evidence discussed in this review, together with the results of virtual screenings, provides a better overview of the proper compounds for further investigations.
Additionally, there are some recently-published review articles that have focused on the effect of flavonoids on one specific target (e.g., ACE-2)or clinical manifestation (cytokine storms or lung injury) of SARS-CoV-2 infection [124-127]. Such points of view can put a focus on the development of natural medicines against one specific viral target; however, we preferred a more general approach in our study. We considered no limitation for antiviral/symptoms relieving mechanisms of flavonoids, and all experimental evidence of flavonoids on the above-mentioned viruses were included.
In conclusion, flavonoids can be considered as promising plant-derived compounds to manage SARS-CoV-2 infection via direct antiviral properties or management of host immune response to viral infection. Future experimental mechanistic and clinical studies are needed to further clarify the role of these compounds in the primary and secondary prevention of SARS-CoV-2 infection.
4. Materials and Methods
Electronic databases, including PubMed, Scopus, and Web of Science, were searched from inception until April 2021 with the following formula:(COVID-19 OR SARS OR MERS OR corona OR HIV OR ebola OR influenza (title/abstract))AND (plant OR extract OR herb OR phytochemical OR flavonoid (all fields). As a supplementary search, the names of popular flavonoids including catechin, quercetin, rutin, hesperidin, hesperetin, naringenin, naringin, baicalin, bailee in, and epigallocatechin gallate(EGCG)were also individually searched in order to collect all related papers. After excluding duplicates, primary retrieved results were screened by two independent investigators based on the title and abstract. Selected papers were then checked based on their full text. Inclusion criteria were any in vitro or in vivo study in which the antiviral effect and mechanism of a flavonoid were evaluated. Studies on phytochemicals other than flavonoids, antiviral assessments of flavonoids without clarifying the mechanisms, and studies with non-English full-texts were excluded from our review. In silico studies were excluded unless coupled with an in vitro/in vivo experiment. We also did not discuss antiviral mechanisms such as inhibition of hemagglutinin and neuraminidase of influenza virus since these proteins are not mutual with SARS-CoV-2 and cannot be extrapolated to this virus. Those studies included in the final article are summarized in Table 1.
References
1. Huang, Y.F.; Bai, C.; He, F.; Xie, Y.; Zhou, H. Review on the potential action mechanisms of Chinese medicines in treating Coronavirus Disease 2019 (COVID-19). Pharmacol. Res. 2020, 158, 104939. [CrossRef]
2. Samieefar, N.; Yari Boroujeni, R.; Jamee, M.; Lotfifi, M.; Golabchi, M.R.; Afshar, A.; Miri, H.; Khazeei Tabari, M.A.; Darzi, P.; Abdullatif Khafaie, M.; et al. Country Quarantine During COVID-19: Critical or Not? Disaster Med. Public Health Prep. 2020, 1–2. [CrossRef] [PubMed]
3. Park, S.E. Epidemiology, virology, and clinical features of severe acute respiratory syndrome -coronavirus-2 (SARS-CoV-2; Coronavirus Disease-19). Clin. Exp. Pediatr. 2020, 63, 119–124. [CrossRef] [PubMed]
4. Singhal, T. A review of coronavirus disease-2019 (COVID-19). Indian J. Pediatr. 2020, 87, 281–286. [CrossRef]
5. Novel, C.P.E.R.E. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China. Zhonghua Liu Xing Bing Xue Za Zhi 2020, 41, 145. [CrossRef]
6. Bosch, B.J.; Van der Zee, R.; De Haan, C.A.; Rottier, P.J.M. The coronavirus spike protein is a class I virus fusion protein: Structural and functional characterization of the fusion core complex. J. Virol. 2003, 77, 8801–8811. [CrossRef]
7. Li, H.Y.; Li, F.; Sun, H.Z.; Qian, Z.M. Membrane-inserted conformation of transmembrane domain 4 of divalent-metal transporter. Biochem. J. 2003, 372, 757–766. [CrossRef] [PubMed]
8. Lu, R.; Zhao, X.; Li, J.; Niu, P.; Yang, B.; Wu, H.; Wang, W.; Song, H.; Huang, B.; Zhu, N.; et al. Genomic characterization and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet 2020, 395, 565–574. [CrossRef]
9. Khazeei Tabari, M.A.; Khoshhal, H.; Tafazoli, A.; Khandan, M.; Bagheri, A. Applying computer simulations in battling with COVID-19, using pre-analyzed molecular and chemical data to face the pandemic. Inf. Med. Unlocked 2020, 21, 100458. [CrossRef]
10. Chan, J.F.; Kok, K.H.; Zhu, Z.; Chu, H.; To, K.K.; Yuan, S.; Yuen, K.Y. Genomic characterization of the 2019 novel humanpathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerg. Microbes Infect. 2020, 9, 221–236. [CrossRef]
11. Grein, J.; Ohmagari, N.; Shin, D.; Diaz, G.; Asperges, E.; Castagna, A.; Feldt, T.; Green, G.; Green, M.L.; Lescure, F.X.; et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N. Engl. J. Med. 2020. [CrossRef] [PubMed]
12. Sissoko, D.; Laouenan, C.; Folkesson, E.; M’lebing, A.B.; Beavogui, A.H.; Baize, S.; Camara, A.M.; Maes, P.; Shepherd, S.; Danel, C. Experimental treatment with favipiravir for Ebola virus disease (the JIKI Trial): A historically controlled, single-arm proof-of-concept trial in Guinea. PLoS. Med. 2016,
