Small molecules targeting severe acute respiratory syndrome human coronavirus

Wu, Ching‐Yi; Jan, Jia Tsrong; Hwa, Shiou; Kuo, C.J.; Juan, Hsueh‐Fen; Cheng, Yih Shyun E.; Hsu, Hsien Hua; Huang, Hsuan Cheng; Wu, Dawei; Brik, Ashraf; Liang, Fu Sen; Liu, Rai Shung; Fang, Jim‐Min; Chen, Shui Tein; Liang, Po Huang; Wong, Chi Huey

doi:10.1073/pnas.0403596101

Cited by 483 publications

(440 citation statements)

References 47 publications

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“…The selective index (SI), the ratio of CC 50 to EC 50 , was also calculated to demonstrate the potency of anti-SARS-CoV activity of test compounds ( valinomycin (SI ) 41.4), determined in parallel in this study and previously reported. 10 Inhibition of SARS-CoV 3CL Protease Activity. The proteolytic cleavage of polyprotein at specific sites by 3CL protease is essential for the replication of SARS-CoV.…”

Section: Resultsmentioning

confidence: 99%

“…Once these values were established, the SI (selective index) value was calculated from the ratio of CC 50 to EC 50 as an indicator of the potency of these compounds. In comparison to the positive controls, niclosamide (21) 28,29 and valinomycin (22), 10 most of the compounds with potent activity against CPE also exhibited marked inhibitory effects on SARS-CoV replication. The SI values (Table 2) for ferruginol (1), dehydroabieta-7-one (2), 8 -hydroxyabieta-9(11),13-dien-12-one) (5), 7 -hydroxydeoxycryptojaponol (6), 3 ,12-diacetoxyabieta-6,8,11,13-tetraene (8), pinusolidic acid (9), forskolin (10), betulonic acid (14), and …”

Section: Discussionmentioning

confidence: 99%

“…Glycyrrhizin from licorice roots has been shown to inhibit SARS-CoV replication with a 50% effective concentration (EC 50 ) of 365 µM, 6 and a number of glycyrrhizin derivatives have been shown to possess modestly higher antiviral bioactivity. 10,11 Calpain inhibitors, such as Val-Leu-CHO (calpain inhibitor VI) and Z-Val-Phe-Ala-CHO (calpain inhibitor III), have also been shown to be potent inhibitors of SARS-CoV replication. 12 A number of protein molecules encoded by the SARS-CoV genome are potential targets for chemotherapeutic inhibition of viral infection, and replication.…”

Section: Introductionmentioning

confidence: 99%

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Specific Plant Terpenoids and Lignoids Possess Potent Antiviral Activities against Severe Acute Respiratory Syndrome Coronavirus

et al. 2007

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In this study, 221 phytocompounds were evaluated for activity against anti-severe acute respiratory syndrome associated coronavirus (SARS-CoV) activities using a cell-based assay measuring SARS-CoV-induced cytopathogenic effect on Vero E6 cells. Ten diterpenoids (1-10), two sesquiterpenoids (11 and 12), two triterpenoids (13 and 14), five lignoids (15-19), curcumin (20), and reference controls niclosamide (21) and valinomycin (22) were potent inhibitors at concentrations between 3.3 and 10 µM. The concentrations of the 22 compounds to inhibit 50% of Vero E6 cell proliferation (CC 50 ) and viral replication (EC 50 ) were measured. The selective index values (SI ) CC 50 /EC 50 ) of the most potent compounds 1, 5, 6, 8, 14, and 16 were 58, >510, 111, 193, 180, and >667, respectively. Betulinic acid (13) and savinin (16) were competitive inhibitors of SARS-CoV 3CL protease with K i values ) 8.2 ( 0.7 and 9.1 ( 2.4 µM, respectively. Our findings suggest that specific abietane-type diterpenoids and lignoids exhibit strong anti-SARS-CoV effects.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Specific Plant Terpenoids and Lignoids Possess Potent Antiviral Activities against Severe Acute Respiratory Syndrome Coronavirus

et al. 2007

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“…Total protein was extracted at 4 or 12 hpi from 5 ml of infected protoplasts (32) and quantified by the Coomassie dye-binding assay (Bio-Rad, Hercules, CA) (33). The accumulation levels of TMV CP in the protoplasts were determined by ELISA (34) and Western blot analysis (35).…”

Section: Methodsmentioning

confidence: 99%

Seco -pregnane steroids target the subgenomic RNA of alphavirus-like RNA viruses

Wang²,

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Plants have evolved multiple mechanisms to selectively suppress pathogens by production of secondary metabolites with antimicrobial activities. Therefore, direct selections for antiviral compounds from plants can be used to identify new agents with potent antiviral activity but not toxic to hosts. Here, we provide evidence that a class of compounds, seco-pregnane steroid glaucogenin C and its monosugar-glycoside cynatratoside A of Strobilanthes cusia and three new pantasugar-glycosides of glaucogenin C of Cynanchum paniculatum, are effective and selective inhibitors to alphavirus-like positive-strand RNA viruses including plant-infecting tobacco mosaic virus (TMV) and animal-infecting Sindbis virus (SINV), eastern equine encephalitis virus, and Getah virus, but not to other RNA or DNA viruses, yet they were not toxic to host cells. In vivo administration of the compounds protected BALB/c mice from lethal SINV infection without adverse effects on the mice. Using TMV and SINV as models, studies on the action mechanism revealed that the compounds predominantly suppress the expression of viral subgenomic RNA(s) without affecting the accumulation of viral genomic RNA. Our work suggested that the viral subgenomic RNA could be a new target for the discovery of antiviral drugs, and that seco-pregnane steroid and its four glycosides found in the two medicinal herbs have the potential for further development as antiviral agents against alphavirus-like positive-strand RNA viruses.antiviral drugs ͉ Strobilanthes cusia ͉ Cynanchum atratum V iruses replicate in host cells by hijacking the host-cell metabolic machinery. It is therefore difficult for antiviral therapies to inhibit only viral functions but spare host cellular processes. Nevertheless, great progress has been achieved over the past decades in antiviral research and therapy to reduce morbidity and mortality in virus-infected individuals (1, 2), and many antiviral drugs have been approved in recent years, most of which targeted either viral proteins or host cellular proteins. However, some of these compounds might induce the resistance of viruses to them and cause cell toxicity (3-5). The continuing emergence of highly pathogenic viruses like avian influenza viruses and severe acute respiratory syndrome coronavirus underscores the importance of advancing the search for effective antiviral agents. Plants have evolved constitutive and inducible defense mechanisms by producing a vast array of secondary metabolites against various microbial pathogens (6). Many herbaceous plants have been used in traditional Chinese medicine to treat viral diseases (7). It is conceivable that antiviral compounds would occur in plants as part of their innate defense arsenal, and the vast assortment of secondary metabolites could serve as a large pool for screening for previously undescribed antiviral compounds with a selective target spectrum and nontoxic to the host plants. Here, we provide evidence that a class of compounds, the seco-pregnane steroid and its glycosides from Strobilanthe...

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“…Because proteolytic processing is essential for the generation of a functional replication complex, 3CL pro and PL pro are potentially effective targets for anti-SARS drugs. Most efforts reported to date have focused on the development of 3CL pro inhibitors, which have been identified in both synthetic peptidyl libraries [9][10][11] and natural derived libraries. 12,13) Fewer inhibitors of PL pro have been studied, and those that have been studied include thiopurine analogs and benzamide derivatives.…”

Section: Diarylheptanoids From Alnus Japonica Inhibit Papain-like Promentioning

confidence: 99%

Diarylheptanoids from <i>Alnus japonica</i> Inhibit Papain-Like Protease of Severe Acute Respiratory Syndrome Coronavirus

Park

Jeong

Kim

et al. 2012

Biological & Pharmaceutical Bulletin

160

133

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The papain-like protease (PL pro ), which controls replication of the severe acute respiratory syndrome coronavirus (SARS-CoV), has been identified as a potential drug target for the treatment of SARS. An intensive hunt for effective anti-SARS drugs has been undertaken by screening for natural product inhibitors that target SARS-CoV PL pro . In this study, diarylheptanoids 1-9 were isolated from Alnus japonica, and the inhibitory activities of these compounds against PL pro were determined. Of the isolated diarylheptanoids, hirsutenone (2) showed the most potent PL pro inhibitory activity, with an inhibitory concentration (IC 50 ) value of 4.1 µM. Structure-activity analysis showed that catechol and α,β-unsaturated carbonyl moiety in the molecule were the key requirement for SARS-CoV cysteine protease inhibition.

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Small molecules targeting severe acute respiratory syndrome human coronavirus

Cited by 483 publications

References 47 publications

Specific Plant Terpenoids and Lignoids Possess Potent Antiviral Activities against Severe Acute Respiratory Syndrome Coronavirus

Specific Plant Terpenoids and Lignoids Possess Potent Antiviral Activities against Severe Acute Respiratory Syndrome Coronavirus

Seco -pregnane steroids target the subgenomic RNA of alphavirus-like RNA viruses

Diarylheptanoids from <i>Alnus japonica</i> Inhibit Papain-Like Protease of Severe Acute Respiratory Syndrome Coronavirus

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