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. 2013 Jul 1;21(13):3730-7.
doi: 10.1016/j.bmc.2013.04.026. Epub 2013 Apr 22.

Dieckol, a SARS-CoV 3CL(pro) inhibitor, isolated from the edible brown algae Ecklonia cava

Ji-Young Park  1 , Jang Hoon Kim, Jung Min Kwon, Hyung-Jun Kwon, Hyung Jae Jeong, Young Min Kim, Doman Kim, Woo Song Lee, Young Bae Ryu
Affiliations

Dieckol, a SARS-CoV 3CL(pro) inhibitor, isolated from the edible brown algae Ecklonia cava

Ji-Young Park et al. Bioorg Med Chem. .

Abstract

SARS-CoV 3CL(pro) plays an important role in viral replication. In this study, we performed a biological evaluation on nine phlorotannins isolated from the edible brown algae Ecklonia cava. The nine isolated phlorotannins (1-9), except phloroglucinol (1), possessed SARS-CoV 3CL(pro) inhibitory activities in a dose-dependently and competitive manner. Of these phlorotannins (1-9), two eckol groups with a diphenyl ether linked dieckol (8) showed the most potent SARS-CoV 3CL(pro) trans/cis-cleavage inhibitory effects (IC(50)s = 2.7 and 68.1 μM, respectively). This is the first report of a (8) phlorotannin chemotype significantly blocking the cleavage of SARS-CoV 3CL(pro) in a cell-based assay with no toxicity. Furthermore, dieckol (8) exhibited a high association rate in the SPR sensorgram and formed extremely strong hydrogen bonds to the catalytic dyad (Cys145 and His41) of the SARS-CoV 3CL(pro).

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Figures

None
Graphical abstract
Figure 1
Figure 1
Chemical structures of isolated phlorotanins from Ecklonia cava.
Figure 2
Figure 2
(A) Effects of compounds 1–9 on the activity of SARS-CoV 3CLpro for proteolysis of substrate. (B) The catalytic activity of SARS-CoV 3CLpro as function of enzyme concentration at different concentrations of compound 8. (C) Lineweaver–Burk plots for inhibition of dieckol (8) on SARS-CoV 3CLpro for the proteolysis of substrate. The values of KM and Vmax on the concentrations of compound 8 (inset).
Figure 3
Figure 3
Inhibition of the cell-based cis-cleavage of the SARS-CoV 3CLpro by the isolated phlorotannins (2–9).
Figure 4
Figure 4
(A) Sensorgrams for the interaction of dieckol (8) with SARS-CoV 3CLpro. (B) The binding pose of dieckol (8) in SARS-CoV 3CLpro. Ribbon plots of dieckol (8) complexed to 3CLpro with hydrogen bonding.
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