title: Tanshinones as selective and slow-binding inhibitors for SARS-CoV cysteine proteases.
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.
authors.affiliation: Infection Control Research Center, Korea Research Institute of Bioscience and Biotechnology, KRIBB, Jeongeup 580-185, Republic of Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Park
authors.forename: Jang Hoon
authors.initials: JH
authors.lastname: Kim
authors.forename: Young Min
authors.initials: YM
authors.lastname: Kim
authors.forename: Hyung Jae
authors.initials: HJ
authors.lastname: Jeong
authors.forename: Dae Wook
authors.initials: DW
authors.lastname: Kim
authors.forename: Ki Hun
authors.initials: KH
authors.lastname: Park
authors.forename: Hyung-Jun
authors.initials: HJ
authors.lastname: Kwon
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Park
authors.forename: Woo Song
authors.initials: WS
authors.lastname: Lee
authors.forename: Young Bae
authors.initials: YB
authors.lastname: Ryu
mesh_terms: D045784:Abietanes / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D011485:Protein Binding; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects / Q000201:enzymology*; D027561:Salvia miltiorrhiza / Q000737:chemistry*; D045169:Severe Acute Respiratory Syndrome / Q000188:drug therapy / Q000201:enzymology; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D045784:Abietanes; D015853:Cysteine Proteinase Inhibitors; C021751:tanshinone