The papain-like protease (PLP) is an IFN antagonist that constitutes a domain of the replicase polyprotein and, therefore, may be active at an early stage of the replication cycle to antagonize an upstream step of IFN induction. Additionally, unlike accessory proteins, which can vary greatly between CoV species, maintenance of PLP catalytic activity is critical to viral replication and is therefore conserved across all CoVs. The coronavirus PLP proteins are multifunctional and encode a catalytic triad domain that catalyzes site-specific peptide cleavage of the viral polyprotein and the removal of both ubiquitin and IFN stimulated gene (ISG) 15 post-translational modifications. PLP protease activity catalyzes the processing of the replicase polyprotein at cleavage sites between nsp1/nsp2, nsp2/nsp3, and nsp3/nsp4.
|Tanshinone IIB (TSB), a natural product isolated and purified from the roots of Salvia miltiorrhiza, can significantly inhibit the DNA laddering, cytotoxicity and apoptosis of rat cortical neurons induced by staurosporine in a concentration-dependent manner. Tanshinone IIB showed inhibitory effect on PL(pro) with IC50 value of 10.7μM and less inhibitory effect on 3CLpro with IC50 value of 24.8μM.
|Tanshinone IIA sulfonate sodium is a water-soluble derivative of tanshinone IIA, which acts as an inhibitor of store-operated Ca2+entry (SOCE), and is used to treat cardiovascular disorders.
|Tanshinone IIA is a naturally occuring cardioprotective agent which can inhibit NF-κB and AP-1 DNA binding and display antioxidant and anti-inflammatory properties. Tanshinone IIA showed inhibitory effect on PL(pro) with IC50 value of 1.6μM and less inhibitory effect on 3CLpro with IC50 value of 89.1μM.
|Tanshinone I, an active principle isolated from the roots of Salvia miltiorrhiza (Danshen), is an inhibitor of type IIA human recombinant sPLA2 and rabbit recombinant cPLA2 with IC50s of 11 μM and 82 μM, respectively, is structurally similar to tanshinone IIA and may possess similar cytotoxic effects on tumor cells. Tanshinone I showed inhibitory effect on PL(pro) with IC50 value of 8.8μM and less inhibitory effect on 3CLpro with IC50 value of 38.7μM.
|Rosmariquinone showed inhibitory effect on PL(pro) and 3CLpro with IC50 values of 30μM and 21.1μM, respectively.
|NSC158011 was found capable of inhibiting the protease activity of PLpro in cell-based assays; however, it was unsuccessful at blocking SARS-CoV viral replication.
|Methyl tanshinonate showed inhibitory effect on PL(pro) with IC50 value of 9.2μM and less inhibitory effect on 3CLpro with IC50 value of 21.1μM.
|Hirsutenone, a natural product isolated and purified from the eaves of Alnus nepalensis, exhibits anti-cancer effect against prostate cancer through a direct physical inhibition of Akt1/2, attenuates adipogenesis by directly targeting PI3K and ERK during MCE in 3T3-L1 preadipocytes, underscoring the potential therapeutic application of Hirsutenone in preventing obesity, and may exert a preventive effect against microbial endotoxin lipopolysaccharide-induced inflammatory skin diseases through inhibition of ERK pathway-mediated NF-kappaB activation. Hirsutenone showed potent PL(pro) inhibitory activity with IC50 value of 4.1µM.
|GRL0617 is a noncovalent lead inhibitor of Plpro. It inhibited SARS-CoV viral replication in Vero E6 cells with an EC50 of 15μM。
|Dihydrotanshinone I, a natural product isolated and purified from the roots of Salvia miltiorrhiza Bge., exhibits dose-dependent inhibition towards HLM-catalyzed propofol glucuronidation. Dihydrotanshinone I showed inhibitory effect on PL(pro) with IC50 value of 4.9μM and less inhibitory effect on 3CLpro with IC50 value of 14.4μM.
|Cryptotanshinone is a potent STAT3 inhibitor (IC50 =4.6 μM) and inhibits STAT3 Tyr705 phosphorylation in DU145 prostate cancer cells. Cryptotanshinone showed inhibitory effect on PL(pro) with IC50 value of 0.8μM and slight inhibitory effect on 3CLpro with IC50 value of 226.7μM.
|6-Thioguanine belongs to the thiopurine family of drugs that also include mercaptopurine and azathioprine, which are examples of antimetabolites, and is a purine analogue of the nucleobase guanine. It was found to inhibit SARS-CoV PLpro. 6-Thioguanine disrupts cytosine methylation by DNA methyltransferases in vitro and acts as a DNA demethylating agent in vivo.
|6-Mercaptopurine Monohydrate inhibits the de novo purine synthesis through incorporation of thiopurine methyltransferase metabolites into DNA and RNA, it is a widely used antileukemic agent and immunosuppressive drug. 6-mercaptopurine was found to inhibit SARS-CoV PLpro.
|6-Mercaptopurine inhibits the de novo purine synthesis through interference with DNA and RNA synthesis, it's an immunosuppressive and antileukemic drug. 6-mercaptopurine was found to inhibit SARS-CoV PLpro.