Discovery of Potent Anilide Inhibitors against the Severe Acute Respiratory Syndrome 3CL Protease

Shie, Jiun‐Jie; Fang, Jim‐Min; Kuo, Cheng-Tzu; Kuo, Tun-Hsun; Liang, Po‐Huang; Huang, Hsin-I; Yang, Wen‐Bin; Lin, Chun‐Hung; Chen, Jiun-Ling; Wu, Yin-Ta; Wong, Chi‐Huey

doi:10.1021/jm050184y

Cited by 91 publications

(77 citation statements)

References 22 publications

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“…Jain and colleagues reported a series of keto-glutamine analogues with a phthalhydraido group at the α-position, whose derivatives are known HAV 3C inhibitors, could act as reversible inhibitors against SARS M pro with IC 50 ranging from 0.6 to 70 µM [80]. 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].…”

Section: Ab Initio Inhibitor Designmentioning

confidence: 99%

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

Yang¹,

Bartlam²,

Rao

2006

CPD

169

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: 99%

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

Yang¹,

Bartlam²,

Rao

2006

CPD

169

144

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“…Although AG7088 has no detectable or very weak inhibitory activity against SARS 3C-like proteinase, some of the derivatives bind to the enzyme with IC 50 of around 11 µM in the in vitro FRET assay using 14mer peptide substrate. Shie et al [58] discovered that anilide compounds act as potent inhibitors in the in vitro FRET assay and the most active compound gives K i of 0.03 µM. Bacha et al [59] designed bifunctional boronic acid compounds to bind with the serine cluster (Ser139, Ser144 and Ser147) near the active site cavity and the compounds inhibited SARS 3C-like proteinase as strong as 40 nM.…”

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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“…They can be categorized as covalent peptidomimetic, non-covalent peptidomimetic, and non-peptidic. [10] Unlike 3CLpro, the development of PLpro inhibitors has been very limited until recently, despite its essential role in SARS viral replication. In addition to our own work, [11] two very different types of PLpro inhibitors have been reported in recent years.…”

Section: Introductionmentioning

confidence: 99%

Synergistic Inhibitor Binding to the Papain‐Like Protease of Human SARS Coronavirus: Mechanistic and Inhibitor Design Implications

et al. 2013

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We have previously developed two potent chemical classes that inhibit the essential papain-like protease (PLpro) of severe acute respiratory syndrome coronavirus (SARS-CoV). In this study, we applied a novel approach to identify small fragments that act synergistically with these inhibitors. A fragment library was screened in combination with four previously developed lead inhibitors by fluorescence-based enzymatic assays. Several fragment compounds synergistically enhanced the inhibitory activity of the lead inhibitors by approximately an order of magnitude. Surface plasmon resonance (SPR) measurements showed that three fragments bind specifically to the PLpro enzyme. Mode of inhibition, computational solvent mapping, and molecular docking studies suggest that these fragments bind adjacent to the binding site of the lead inhibitors and further stabilize the inhibitor-bound state. We propose potential next generation compounds based upon a computational, fragment-merging approach. This approach provides an alternative strategy for lead optimization in cases where direct co-crystallization is difficult.

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Discovery of Potent Anilide Inhibitors against the Severe Acute Respiratory Syndrome 3CL Protease

Cited by 91 publications

References 22 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

Synergistic Inhibitor Binding to the Papain‐Like Protease of Human SARS Coronavirus: Mechanistic and Inhibitor Design Implications

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