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Mar Drugs
2020 Nov 05;1811:. doi: 10.3390/md18110550.
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Antiviral Potential of Sea Urchin Aminated Spinochromes against Herpes Simplex Virus Type 1.
Mishchenko NP
,
Krylova NV
,
Iunikhina OV
,
Vasileva EA
,
Likhatskaya GN
,
Pislyagin EA
,
Tarbeeva DV
,
Dmitrenok PS
,
Fedoreyev SA
.
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Herpes simplex virus type 1 (HSV-1) is one of the most prevalent pathogens worldwide requiring the search for new candidates for the creation of antiherpetic drugs. The ability of sea urchin spinochromes-echinochrome A (EchA) and its aminated analogues, echinamines A (EamA) and B (EamB)-to inhibit different stages of HSV-1 infection in Vero cells and to reduce the virus-induced production of reactive oxygen species (ROS) was studied. We found that spinochromes exhibited maximum antiviral activity when HSV-1 was pretreated with these compounds, which indicated the direct effect of spinochromes on HSV-1 particles. EamB and EamA both showed the highest virucidal activity by inhibiting the HSV-1 plaque formation, with a selectivity index (SI) of 80.6 and 50.3, respectively, and a reduction in HSV-1 attachment to cells (SI of 8.5 and 5.8, respectively). EamA and EamB considerably suppressed the early induction of ROS due to the virus infection. The ability of the tested compounds to directly bind to the surface glycoprotein, gD, of HSV-1 was established in silico. The dock score of EchA, EamA, and EamB was -4.75, -5.09, and -5.19 kcal/mol, respectively, which correlated with the SI of the virucidal action of these compounds and explained their ability to suppress the attachment and penetration of the virus into the cells.
Figure 1. (A) Structural formulae of the studied spinochromes. Absorption spectra of the studied spinochromes (0.02 mg/mL) in (B) acidified ethanol (pH 1.0), (C) phosphate buffered saline (PBS); 0.01 M, pH 7.2, and (D) Dulbecco’s Modified Eagle’s Medium (DMEM) (pH 7.2). Compound spectra were recorded in comparison to the corresponding solvent.
Figure 2. Effects of HSV-1 and spinochromes on reactive oxygen species (ROS) levels in Vero cells. The DCF-DA (2′,7′-dichlorofluorescein diacetate) assay was used to measure the cellular ROS. (A) Dynamics of HSV-1-induced intracellular ROS levels compared to uninfected cells (control). Data are presented as the mean ± SD of three independent experiments. * p ≤ 0.05 compared with the control. (B) Effects of the studied spinochromes (5 µg/mL) on the ROS levels in uninfected cells. (C) Effects of HSV-1 (100 PFU/mL) on ROS levels after incubation for 1 h with spinochromes (5 µg/mL). The results include data from three experiments (mean ± SD). * p ≤ 0.05 compared with HSV-1-infected cells.
Figure 3. Molecular docking of spinochromes with gD. (A) Subsites 1 and 2 of binding of spinochromes to gD. Spinochrome structures are shown in colour as balls and sticks. The gD molecule is shown as a ribbon. (B) Molecular surface of gD in the binding sites of the spinochromes. Site 1: EchA (turquoise), EamA (beige), EamB (brown); Site 2: EchA (turquoise), EamA (beige), EamB (yellow). The colour shows the molecular surface of gD: H-bonding (pink), hydrophobic (green), and mild polar (blue).
Figure 4. 2D diagrams of EchA, EamA, and EamB contacts with the HSV-1 glycoprotein gD. Abbreviations of aminoacids: alanine (Ala); arginine (Arg); aspartic acid (Asp); asparagine (Asn); glutamine (Gln); glycine (Gly); leucine (Leu); phenylalanine (Phe); serine (Ser); valine (Val).
Figure 5. Molecular docking of the 3-O-sulphated heparan sulphate (3-OS HS) tetrasaccharide and the herpes simplex virus type 1 (HSV-1) gD membrane glycoprotein. (A) 3D structure and (B) 2D structure of 3-OS HS obtained using the MOE program. (C) The putative binding site of 3-OS HS and gD HSV-1. (D) 2D diagram of the contacts of 3-OS HS with gD.
Figure 6. (A) Molecular docking of spinochromes into a potential binding site of the 3-OS HS tetrasaccharide and the HSV-1 gD membrane glycoprotein. The electrostatic potential of the gD molecular surface was calculated using the MOE 2019.01 program. The spinochrome structures are shown as sticks. (B) 2D diagram of contacts of EchA, EamA, and EamB protomers with gD.
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