Tanshinones as selective and slow-binding inhibitors for SARS-CoV cysteine proteases - PubMed (original) (raw)

Tanshinones as selective and slow-binding inhibitors for SARS-CoV cysteine proteases

Ji-Young Park et al. Bioorg Med Chem. 2012.

Abstract

In the search for anti-SARS-CoV, tanshinones derived from Salvia miltiorrhiza were found to be specific and selective inhibitors for the SARS-CoV 3CL(pro) and PL(pro), viral cysteine proteases. A literature search for studies involving the seven isolated tanshinone hits showed that at present, none have been identified as coronaviral protease inhibitors. We have identified that all of the isolated tanshinones are good inhibitors of both cysteine proteases. However, their activity was slightly affected by subtle changes in structure and targeting enzymes. All isolated compounds (1-7) act as time dependent inhibitors of PL(pro), but no improved inhibition was observed following preincubation with the 3CL(pro). In a detail kinetic mechanism study, all of the tanshinones except rosmariquinone (7) were identified as noncompetitive enzyme isomerization inhibitors. However, rosmariquinone (7) showed a different kinetic mechanism through mixed-type simple reversible slow-binding inhibition. Furthermore, tanshinone I (5) exhibited the most potent nanomolar level inhibitory activity toward deubiquitinating (IC(50)=0.7 μM). Additionally, the inhibition is selective because these compounds do not exert significant inhibitory effects against other proteases including chymotrysin, papain, and HIV protease. These findings provide potential inhibitors for SARS-CoV viral infection and replication.

Copyright © 2012 Elsevier Ltd. All rights reserved.

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Figures

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Graphical abstract

Figure 1

Figure 1

Chemical structures of isolated tanshinones from S. miltiorrhiza lipophilic fraction and representative hydrophilic compound, salvianolic acid B.

Figure 2

Figure 2

(A) Effects of compounds 1–7 on the activity of SARS-CoV 3CLpro for proteolysis of substrate. (B) SARS-CoV PLpro inhibition as a function of preincubation time for compounds 1–7 at IC50 value.

Figure 3

Figure 3

(A) Time course of substrate proteolyzed by PLpro in the presence of compound 4. (B) Dependence of the values for _k_obs on the concentrations of compound 4. (C) Dependence of the values for _k_obs on the concentrations of compound 7. The _k_obs values were fitted to Eqs. (2), (3).

Figure 4

Figure 4

Scheme for time dependent enzyme inhibition. The upper part denoted the turnover of the enzyme in the absence of inhibition. The lower part illustrates the equilibrium for a slow-binding inhibition process. In simple reversible slow-binding inhibition process that the low values of _k_3 and _k_4 relative to enzyme turnover. In enzyme isomerisation, an initial binding of the inhibitor to the enzyme leads to formation of the EI complex, which undergoes an isomerisation of the enzyme to form the new complex E∗I.

Figure 5

Figure 5

Dixon plots for inhibition of compounds 4 and 7 on SARS-CoV PLpro for the proteolysis of substrate. (A) Noncompetitive inhibition of PLpro by compound 4. (B) Mixed-type inhibition of PLpro by compound 7.

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