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. 2017 Dec;32(1):504-515.
doi: 10.1080/14756366.2016.1265519.

Evaluation of polyphenols from Broussonetia papyrifera as coronavirus protease inhibitors

Ji-Young Park  1 , Heung Joo Yuk  2 , Hyung Won Ryu  2 , Su Hwan Lim  1 , Kyung Su Kim  1 , Ki Hun Park  3 , Young Bae Ryu  1 , Woo Song Lee  1
Affiliations

Evaluation of polyphenols from Broussonetia papyrifera as coronavirus protease inhibitors

Ji-Young Park et al. J Enzyme Inhib Med Chem. 2017 Dec.

Abstract

The current study was designed to assess the inhibitory activity of Broussonetia papyrifera-derived polyphenols against 3-chymotrypsin-like and papain-like coronavirus cysteine proteases. The isolated compounds were broussochalcone B (1), broussochalcone A (2), 4-hydroxyisolonchocarpin (3), papyriflavonol A (4), 3'-(3-methylbut-2-enyl)-3',4,7-trihydroxyflavane (5), kazinol A (6), kazinol B (7), broussoflavan A (8), kazinol F (9), and kazinol J (10). All polyphenols were more potent against papain-like protease (PLpro) than against 3-chymotripsin-like protease (3CLpro); therefore, we investigated their structural features that were responsible for this selectivity. Compound 4 was the most potent inhibitor of PLpro with an IC50 value of 3.7 μM. The active compounds displayed kinetic behaviors, and the binding constants of their interaction with PLpro were determined from surface plasmon resonance analysis. Our results suggest B. papyrifera constituents as promising candidates for development into potential anti-coronaviral agents.

Keywords: Broussonetia papyrifera; SARS; coronavirus; papain-like protease; polyphenol.

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Figures

Figure 1.
Figure 1.
Chemical structures of isolated compounds from Broussonetia papyrifera.
Figure 2.
Figure 2.
SDS-PAGE of purified MERS-CoV 3CLpro (A) and MERS-CoV PLpro (C); Lineweaver–Burk plots for the determination of Km values against the MERS-CoV 3CLpro (B) and MERS-CoV PLpro (D). (A, C) M, protein molecular-weight markers (kDa); CL, cell lysate; FT, flow-through; W1, 20 mM imidazole wash; E1, E2 and E3, 50, 100 and 200 mM imidazole elution. (B, D) The reaction was done at various substrate concentrations to obtain K m value of the enzyme. SigmaPlot was used to fit the kinetic data using Lineweaver–Burk double reciprocal plots.
Figure 3.
Figure 3.
Effects of compounds 1–10 on the activity of SARS-CoV PLpro for proteolysis of substrates (A; LXGG-AMC, B; Ubiqutin-AMC, C; ISG15-AMC).
Figure 4.
Figure 4.
Graphical determination of the inhibition type for compounds. (A) Lineweaver–Burk plot for the inhibition of compound 2 on SARS-CoV PLpro. (B) Lineweaver–Burk plot for the inhibition of compound 4 on SARS-CoV PLpro.
Figure 5.
Figure 5.
Surface plasmon resonance analysis for the interaction of compounds with SARS-CoV PLpro (A) Normalized refractive index change obtained for different compounds (1, 2, 4 and 10) concentrations. The experiments were carried out in PBS at a 30 μL/mL flow rate. (insert) The linear dependence of the response in function of the concentration of compounds injected over immobilized SARS-CoV PLpro support the idea of nonspecific direct binding. (B) SPR sensogram of the interaction between compounds of 40 μM and SARS-CoV PLpro (left). The K D values for the binding compounds to immobilized SARS-CoV PLpro. k a and k d from where K D were calculated are also shown (right).
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