Evaluation of the virucidal effects of rosmarinic acid against enterovirus 71 infection via in vitro and in vivo study

Abstract

Background Although enterovirus 71 (EV71) is an important public health threat, especially in the Asia-Pacific region, there are still no effective drugs or vaccines to treat and prevent EV71 infection. Therefore, it is critical to develop prophylactic and therapeutic agents against EV71. Rosmarinic acid (RA), a phytochemical, has been discovered to possess a broad spectrum of biological activities. Methods The virucidal effects of RA on EV71 were determined by MTT, western blot, median cell culture infectious dose, apoptosis detection, plaque reduction, semi-quantitative real-time polymerase chain reaction, immunofluorescence detection, molecular docking analysis, and mouse protection assay. Results RA showed a strong protective effect against EV71 infection in human rhabdomyosarcoma cells when the multiplicity of infection was 1, with a low IC 50 value (4.33 ± 0.18 μM) and high therapeutic index (340). RA not only protected cells from EV71-induced cytopathic effects, but also from EV71-induced apoptosis. The results of time-of-addition analysis demonstrated that the inhibitory activity of RA was highest at the early stage of viral infection. Consistent with this, the infectivity of EV71 in the early stage of viral infection also was observed to be limited in neonatal mice treated with RA. Further, molecular docking predicts that RA could replace the natural pocket factor within the VP1 capsid-binding hydrophobic pocket. Conclusions This study suggests that RA has the potential to be developed as an antiviral agent against initial EV71 infection to prevent or reduce EV71-induced pathogenesis and complications, since RA can effectively reduce EV71 infection in the early stages of viral infection.

Rosmarinic acid exhibits broad anti-enterovirus A71 activity by inhibiting the interaction between the five-fold axis of capsid VP1 and cognate sulfated receptors

“…Rosmarinic acid (RA), an ester of caffeic acid and 3,4-dihydroxyphenyllactic acid ( Figure 1A) found in Danshen, exhibits antioxidant, anti-inflammatory, anti-bacterial, and antiviral properties [23][24][25][26]. RA has also been previously shown to possess anti-EV-A71 activity, as it inhibits virus entry [22,27]. However, the underlying molecular mechanism remains uncharacterized.…”

Research on the biological activity of rosemary extracts and its application in food

“…Lin et al [6] found that rosmarinic acid could protect cells from the pathological changes induced by enterovirus 71 (EV71), and the inhibitory activity of rosmarinic acid was the strongest at the early stage of EV71 infection, which could be used as an antiviral drug for EV71 infection in the early stage of treatment. In addition, rosemary extracts can also inhibit the replication of influenza virus and has a therapeutic effect on virus-induced pneumonia injury.…”

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“…In silico study predicts that rosmarinic acid can replace the natural receptacle factor in the VP1 capsid-binding hydrophobic vessel. 29 Rosmarinic acid has an excellent opportunity as an antiviral candidate to inhibit replication and reduce the adverse effects caused by EV71 infection because rosmarinic acid is effective in reducing EV71 viral infection in the early stages. Rosmarinic acid acts in the early stages of viral infection and can target viral particles directly to affect the interaction between virus-P-selectin glycoprotein ligand-1 (PSGL1) and virus-heparan sulfate.…”

“…89 Tanshinone ⅡA inhibits Tat-induced Transactivation of LTR HIV-1 depending on the AMPK-Nampt pathway so that it can be developed into a new anti-HIV agent, 90 oleanolic acid inhibits HIV-1 replication by inhibiting HIV-1 protease activity in vitro, 91,92 and maslinic acid has potent inhibitory activity against HIV-1 proteases. 93 Ladanein Anti-HCV hepatitis C virus (HCV) activity 83 Sinensetin -Treatment of influenza disease with excessive inflammation 31 -Inhibitors of SARS-CoV-2 Guanine-N7 Methyltransferase (in silico study) 77 Cirsimaritin -Inhibitors of COVID-19 main protease (in silico study) 78 -Anti-influenza virus 95 Phenolic Acid 96,43,97,98 Rhamnazin Anti-HCV hepatitis C virus (HCV) activity 99 Rosmarinic acid -Anti enterovirus 71 (EV71) 29,30 -Potential inhibitor of COVID-19 (in silico study) 32,33,73 -Reduces the mortality of mice infected with the Japanese encephalitis virus (JEV) 34 -Inhibit hepatitis B virus replication 36 Caffeic acid -Anti-herpes simplex virus type 1 54 -Inhibition influenza A virus multiplication in vitro 67…”

“…Rosmarinic acid can be developed as a therapy for enterovirus 71 (EV71) infection. 29,30 Sinensetin has the potential as a drug for influenza H1N1 virus infection. 31 Based on an in-silico study, rosmarinic acid is a potent inhibitor of COVID-19; 32,33 rosmarinic acid reduces the mortality of mice infected with the Japanese encephalitis virus (JEV), 34 Water extract of the leaves, flowers, and all the plants in addition to the root of the O. aristatus (0.39 mg/mL) had antiviral activity with a 100% reduction in herpes simplex virus type 1 (HSV-1) plaque, 1 O. aristatus can be developed as an antiherpetic.…”