Synthesis and evaluation of isatin derivatives as effective SARS coronavirus 3CL protease inhibitors

Chen, Li-Rung; Wang, Yu-Chin; Lin, Yi Wen; Chou, Shan-Yen; Chen, Shyh‐Fong; Liu, Lee Tai; Wu, Ying‐Ta; Kuo, C.J.; Chen, Tom Shieh-Shung; Juang, Shin‐Hun

doi:10.1016/j.bmcl.2005.04.027

Cited by 174 publications

(133 citation statements)

References 20 publications

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“…Shie and colleagues reported that an anilide derived from 2-chloro-4-nitroaniline, L-phenylalanine and 4-(dimethylamino) benzoic acid can reversibly inhibit SARS-CoV M pro with a K i of 30 nM [87]. Chen and co-workers reported that a series of isatin (2,3-dioxindole) derivatives, which are known covalent inhibitors against rhinovirus 3C protease, could inhibit SARS-CoV M pro activity [98]. Unfortunately, previous studies have also shown that isatin compounds displayed poor antiviral activity [97], which might limit their use in drug development against SARS-CoV.…”

Section: Ab Initio Inhibitor Designmentioning

confidence: 97%

Drug Design Targeting the Main Protease, the Achilles Heel of Coronaviruses

Yang¹,

Bartlam²,

Rao

2006

CPD

171

144

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Coronaviruses (CoVs), a genus containing about 26 known species to date, cause highly prevalent diseases and are often severe or fatal in humans and animals. In 2003, a previously unknown coronavirus was identified to be the etiological agent of a global outbreak of a form of life-threatening pneumonia called severe acute respiratory syndrome (SARS). No efficacious therapy is currently available, and vaccines and drugs are under development to prevent SARS-CoV infection in many countries. The CoV main protease (M(pro)), which plays a pivotal role in viral gene expression and replication through a highly complex cascade involving the proteolytic processing of replicase polyproteins, is an attractive target for drug design. This review summarizes the recent advances in biological and structural studies, together with development of inhibitors targeting CoV M(pro)s. It is expected that inhibitors targeting CoV M(pro)s could be developed into wide-spectrum antiviral drugs against existing and possible future emerging CoV-associated diseases.

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Section: Ab Initio Inhibitor Designmentioning

confidence: 97%

Drug Design Targeting the Main Protease, the Achilles Heel of Coronaviruses

Yang¹,

Bartlam²,

Rao

2006

CPD

171

144

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“…Our experience with this substrate gave no detectable cleavage activity (unpiblished data). Chen et al [60] started from known rhinovirus 3C protease inhibitors, 2,3-dioxindole compounds, to make a series of derivatives and tested their activity against SARS 3C-like proteinase. Some of the compounds were potent inhibitors with IC 50 values ranging from 0.95 to 17.5 µM.…”

Section: Active Inhibitors Discoveredmentioning

confidence: 99%

Quaternary Structure, Substrate Selectivity and Inhibitor Design for SARS 3C-Like Proteinase

Lai¹,

Han²,

Chen³

et al. 2006

CPD

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The SARS coronavirus 3C-like proteinase is recognized as a potential drug design target for the treatment of severe acute respiratory syndrome. In the past few years, much work has been done to understand the catalytic mechanism of this target protein and to design its selective inhibitors. The protein exists as a dimer/monomer mixture in solution and the dimer was confirmed to be the active species for the enzyme reaction. Quantitative dissociation constants have been reported for the dimer by using analytic ultracentrifuge, gel filtration and enzyme assays. Though the enzyme is a cysteine protease with a chymotrypsin fold, SARS 3C-like proteinase follows the general base catalytic mechanism similar to chymotrypsin. As the enzyme can cut eleven different sites on the viral polyprotein, the substrate specificity has been studied by synthesized peptides corresponding or similar to the cleavage sites on the polyprotein. Predictive model was built for substrate structure and activity relationships and can be applied in inhibitor design. Due to the lack of potential drugs for the treatment of SARS, the discovery of inhibitors against SARS 3C-like proteinase, which can potentially be optimized as drugs appears to be highly desirable. Various groups have been working on inhibitor discovery by virtual screening, compound library screening, modification of existing compounds or natural products. High-throughput in vitro assays, auto-cleavage assays and viral replication assays have been developed for inhibition activity tests. Inhibitors with IC50 values as low as 60 nM have been reported.

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“…Its derivatives were tested as inhibitors for SARS 3CL pro . From a series of synthetic isatin derivatives (12) showing IC 50 = 0.95-17.5 µ M, the best inhibitor found is listed in Table 2 (inhibitor type D), which has an iodo or bromo in the isatin scaffold [63]. The benzothiophenemethyl side chain provides more inhibitory effect than the benzyl, heterocyclic substituted methyl, and other alkyl groups.…”

Section: Isatinmentioning

confidence: 99%

Characterization and Inhibition of SARS-Coronavirus Main Protease

Liang

2006

CTMC

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Severe acute respiratory syndrome (SARS) is an emerging infectious disease caused by a novel human coronavirus (CoV). During the 2003 epidemic, the disease rapidly spread from its origin in southern China to other countries and affected almost 8000 patients, which resulted in about 800 fatalities. A chymotrypsin-like cysteine protease named 3C-like protease (3CLpro) is essential for the life cycle of the SARS-CoV. This main protease is responsible for maturation of functional proteins and represents a key anti-viral target. HPLC and fluorescence-based assays have been used to characterize the protease and to determine the potency of the inhibitors. The fluorogenic method monitoring the increase of fluorescence from the cleavage of a peptide substrate containing an Edans-Dabcyl fluorescence quenching pair at two ends has enabled the use of high throughput screening to speed up the drug discovery process. Several groups of inhibitors have been identified through high throughput screening and rational drug design approaches. Thus, alpha,beta-unsaturated peptidomimetics, anilides, metal-conjugated compounds, boronic acids, quinolinecarboxylate derivatives, thiophenecarboxylates, phthalhydrazide-substituted ketoglutamine analogues, isatin and natural products have been identified as potent inhibitors of the SARS-CoV main protease. The different classes of inhibitors reported in these studies are summarized in this review. Some of these inhibitors could be developed into potential drug candidates, which may provide a solution to combat possible reoccurrence of the SARS and other life-threatening viruses with 3CL proteases.

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Synthesis and evaluation of isatin derivatives as effective SARS coronavirus 3CL protease inhibitors

Cited by 174 publications

References 20 publications

Drug Design Targeting the Main Protease, the Achilles Heel of Coronaviruses

Drug Design Targeting the Main Protease, the Achilles Heel of Coronaviruses

Quaternary Structure, Substrate Selectivity and Inhibitor Design for SARS 3C-Like Proteinase

Characterization and Inhibition of SARS-Coronavirus Main Protease

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