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. 2022 May 18:2022:7953728.
doi: 10.1155/2022/7953728. eCollection 2022.

Antiviral Effect of Polyphenolic Substances in Geranium wilfordii Maxim against HSV-2 Infection Using in vitro and in silico Approaches

Hao Zhang  1   2 , Zhen Li  2 , Chaoqun Li  3 , Renfang Chen  1 , Tao Liu  2 , Yiming Jiang  1
Affiliations

Antiviral Effect of Polyphenolic Substances in Geranium wilfordii Maxim against HSV-2 Infection Using in vitro and in silico Approaches

Hao Zhang et al. Evid Based Complement Alternat Med. .

Abstract

Background: Herpes simplex virus type 2 (HSV-2) infestation was the most widespread STD (sexually transmitted diseases) among humans and was the leading cause of infectious recurrent genital herpes. Existing therapies against HSV-2 did incompletely restrain the comeback of activated HSV-2 infestation. Geranium wilfordii Maxim had long been used as traditional Chinese medicine for treating the diseases owing to its anti-inflammatory and antiviral effects. Herein, the study was designed to investigate the antiviral activity of G.wilfordii and its potential effect in regulating the host's immune response.

Methods: To identify the stage of infection at which the compounds inhibited HSV-2, we performed virucidal, therapeutic, and prophylactic assays. The antiviral efficacy was evaluated by the analysis of viral components HSV-2 gD and VP16. The antiviral activities of these compounds were also evaluated by phenotypic analysis, such as cell proliferation and apoptosis. Molecular docking studies on candidate compounds were done to indicate binding interactions between the compounds and adopted compound targets.

Results: Quercetin, corilagin, and geraniin inhibited the replication of HSV-2, with geraniin showing greater TI. The obtained IC50 value of quercetin was 204.7 μM and TI (IC50/EC50) was 5.1, whereas the obtained IC50 value of corilagin was 118.0 μg/ml and TI was 4.05. Geraniin exhibited prominent antiviral activity with an IC50 of 212.4 μM and an EC50 of 18.37 μM, resulting in a therapeutic index (TI) of 11.56. Geraniin showed important in vitro virucidal activity through blocking viral attachment. Compared with the virus group, the apoptosis rates in quercetin-, corilagin-, and geraniin-treated groups were significantly decreased (p < 0.001).The expressions at the transcription genes of virus own replication key factors (including HSV-2 gD and VP16) and cytokines (including TBK1) of infected cells treated with quercetin, corilagin, and geraniin were inhibited. The in silico approaches demonstrated a high number of potential strong intermolecular interactions as hydrogen bonds between geraniin, corilagin, and the activity site of HSV-2 gD. Molecular docking studies demonstrated the effects of corilagin by targeting TBK1.

Conclusions: Together, these results highlighted the importance of G.wilfordii treatment in HSV-2 infection and underscored its therapeutic potential. However, additional in vitro and in vivo research was required to validate our findings.

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Conflict of interest statement

The authors report that there are no conflicts of interest in this work.

Figures

Figure 1
Figure 1
(a) 3D structures of quercetin. (b) 3D structures of corilagin. (c) 3D structures of geraniin.
Figure 2
Figure 2
(a) TCID50-based virus titer assay. (b) Determination of the concentration of virus dilutions to meet the experimental conditions. (c) Determination of virus adsorption time to meet experimental conditions. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, and ∗∗∗∗p < 0.0001.
Figure 3
Figure 3
The cellular survival rates of HaCaT cells treated with acyclovir, quercetin, corilagin, and geraniin. (a) Aciclovir; (b) Quercetin; (c) Corilagin; and (d) Geraniin. ∗p < 0.05, ∗∗p < 0.01,∗∗∗p < 0.001, and ∗∗∗∗p < 0.0001.
Figure 4
Figure 4
(a) Optimal antiviral concentration of acyclovir. (b) Optimal antiviral concentration of quercetin. (c) Optimal antiviral concentration of corilagin. (d) Optimal antiviral concentration of geraniin.
Figure 5
Figure 5
The cellular survival curves of HaCaT cells treated with acyclovir, quercetin, corilagin, and geraniin. (a) Aciclovir; (b) quercetin; (c) corilagin; and (d) geraniin. The antiviral activities of acyclovir, quercetin, corilagin, and geraniin against HSV-2. (e) Aciclovir; (f) quercetin; (g) corilagin; and (h) geraniin. IC50, 50% inhibitory concentration; EC50, 50% effective concentration; TI, therapeutic index (IC50/EC50 for anti-HSV-2); acyclovir as the positive control. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, and ∗∗∗∗p < 0.0001.
Figure 6
Figure 6
(a) Anti-HSV-2 activity of acyclovir, quercetin, corilagin, and geraniin in therapeutic assay using HaCaT cells. (b) Anti-HSV-2 activity of acyclovir, quercetin, corilagin, and geraniin in virucidal assay using HaCaT cells. (c) Anti-HSV-2 activity of acyclovir, quercetin, corilagin, and geraniin in prophylactic assay using HaCaT cells. Low (L), medium (M), and high (H) markers represented compounds with low, medium, and high doses, respectively. Quercetin doses in the low-, medium-, and high-dose groups were 12.5, 25, and 50 μM, respectively. Corilagin doses in the low-, medium-, and high-dose groups were 12.5, 25 and 50 μg/ml, respectively. Geraniin doses in the low-, medium-, and high-dose groups were 25, 50, and 100 μM，respectively. Differences in the anti-HSV-2 activity of the samples in comparison to the viral control were analyzed by one-way ANOVA (∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, and ∗∗∗∗p < 0.0001).
Figure 7
Figure 7
(a) The representative flow cytometry plots showed proportions of four groups' HaCaT cells after different treatments. (b) A histogram showing quercetin, corilagin, and geraniin treatment inhibited cell apoptosis. (∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, and ∗∗∗∗p < 0.0001).
Figure 8
Figure 8
The mRNA levels of each factor in cells treated with different modes. (a)–(d) Quercetin-treated group. (e)–(h) Corilagin-treated group. (i)–(l) Geraniin-treated group. Virus meant positive control without compound treatment. ACV represented acyclovir-treated group. V1 represented virucidal assay group. V2 represented therapeutic assay group. V3 represented prophylactic assay group. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, and ∗∗∗∗p < 0.0001.
Figure 9
Figure 9
Interactions observed between the ligand molecules and the binding pocket of the HSV-2 gD visualized by Discovery studio. Green colour represented the hydrogen bond interaction between the target and the ligand molecules. (a) 3D interaction pattern of HSV-2 gD-quercetin complex. (b) 2D pattern of HSV-2 gD-quercetin complex. (c) 3D interaction pattern of HSV-2 gD-corilagin complex. (d) 2D pattern of HSV-2 gD-corilagin complex. (e) 3D interaction pattern of HSV-2 gD-geraniin complex. (f) 2D pattern of HSV-2 gD-geraniin complex. (g) 3D interaction pattern of HSV-2 gD-docosanol complex. (h) 2D pattern of HSV-2 gD-docosanol complex.
Figure 10
Figure 10
Interactions observed between the ligand molecules and the binding pocket of the TBK1 visualized by Discovery studio. (a) 3D interaction pattern of TBK1-aciclovir complex. (b) 2D pattern of TBK1-aciclovir complex. (c) 3D interaction pattern of TBK1-quercetin complex. (d) 2D pattern of TBK1-quercetin complex. (e) 3D interaction pattern of TBK1-corilagin complex. (f) 2D pattern of TBK1-corilagin complex. (g) 3D interaction pattern of TBK1-MRT67307 complex. (h) 2D pattern of TBK1-MRT67307 complex.
Figure 11
Figure 11
Interactions observed between the ligand molecules and the binding pocket of the RSAD2 visualized by Discovery studio. (a) 3D interaction pattern of RSAD2-quercetin complex. (b) 2D pattern of RSAD2-quercetin complex. (c) 3D interaction pattern of RSAD2-aciclovir complex. (d) 2D pattern of RSAD2-aciclovir complex.
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