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Article: Design of wide-spectrum inhibitors targeting coronavirus main proteases.

TitleDesign of wide-spectrum inhibitors targeting coronavirus main proteases.
Authors
Issue Date2005
Citation
Plos Biology., 2005, v. 3 n. 10, p. e324 How to Cite?
AbstractThe genus Coronavirus contains about 25 species of coronaviruses (CoVs), which are important pathogens causing highly prevalent diseases and often severe or fatal in humans and animals. No licensed specific drugs are available to prevent their infection. Different host receptors for cellular entry, poorly conserved structural proteins (antigens), and the high mutation and recombination rates of CoVs pose a significant problem in the development of wide-spectrum anti-CoV drugs and vaccines. CoV main proteases (M(pro)s), which are key enzymes in viral gene expression and replication, were revealed to share a highly conservative substrate-recognition pocket by comparison of four crystal structures and a homology model representing all three genetic clusters of the genus Coronavirus. This conclusion was further supported by enzyme activity assays. Mechanism-based irreversible inhibitors were designed, based on this conserved structural region, and a uniform inhibition mechanism was elucidated from the structures of Mpro-inhibitor complexes from severe acute respiratory syndrome-CoV and porcine transmissible gastroenteritis virus. A structure-assisted optimization program has yielded compounds with fast in vitro inactivation of multiple CoV M(pro)s, potent antiviral activity, and extremely low cellular toxicity in cell-based assays. Further modification could rapidly lead to the discovery of a single agent with clinical potential against existing and possible future emerging CoV-related diseases.
Persistent Identifierhttp://hdl.handle.net/10722/157435
ISSN
2015 Impact Factor: 8.668
2015 SCImago Journal Rankings: 5.293
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorYang, Hen_US
dc.contributor.authorXie, Wen_US
dc.contributor.authorXue, Xen_US
dc.contributor.authorYang, Ken_US
dc.contributor.authorMa, Jen_US
dc.contributor.authorLiang, Wen_US
dc.contributor.authorZhao, Qen_US
dc.contributor.authorZhou, Zen_US
dc.contributor.authorPei, Den_US
dc.contributor.authorZiebuhr, Jen_US
dc.contributor.authorHilgenfeld, Ren_US
dc.contributor.authorYuen, KYen_US
dc.contributor.authorWong, Len_US
dc.contributor.authorGao, Gen_US
dc.contributor.authorChen, Sen_US
dc.contributor.authorChen, Zen_US
dc.contributor.authorMa, Den_US
dc.contributor.authorBartlam, Men_US
dc.contributor.authorRao, Zen_US
dc.date.accessioned2012-08-08T08:49:57Z-
dc.date.available2012-08-08T08:49:57Z-
dc.date.issued2005en_US
dc.identifier.citationPlos Biology., 2005, v. 3 n. 10, p. e324en_US
dc.identifier.issn1545-7885en_US
dc.identifier.urihttp://hdl.handle.net/10722/157435-
dc.description.abstractThe genus Coronavirus contains about 25 species of coronaviruses (CoVs), which are important pathogens causing highly prevalent diseases and often severe or fatal in humans and animals. No licensed specific drugs are available to prevent their infection. Different host receptors for cellular entry, poorly conserved structural proteins (antigens), and the high mutation and recombination rates of CoVs pose a significant problem in the development of wide-spectrum anti-CoV drugs and vaccines. CoV main proteases (M(pro)s), which are key enzymes in viral gene expression and replication, were revealed to share a highly conservative substrate-recognition pocket by comparison of four crystal structures and a homology model representing all three genetic clusters of the genus Coronavirus. This conclusion was further supported by enzyme activity assays. Mechanism-based irreversible inhibitors were designed, based on this conserved structural region, and a uniform inhibition mechanism was elucidated from the structures of Mpro-inhibitor complexes from severe acute respiratory syndrome-CoV and porcine transmissible gastroenteritis virus. A structure-assisted optimization program has yielded compounds with fast in vitro inactivation of multiple CoV M(pro)s, potent antiviral activity, and extremely low cellular toxicity in cell-based assays. Further modification could rapidly lead to the discovery of a single agent with clinical potential against existing and possible future emerging CoV-related diseases.en_US
dc.languageengen_US
dc.relation.ispartofPLoS biology.en_US
dc.subject.meshAnimalsen_US
dc.subject.meshAntiviral Agents - Chemical Synthesis - Pharmacologyen_US
dc.subject.meshBinding Sitesen_US
dc.subject.meshCoronavirus - Enzymologyen_US
dc.subject.meshCrystallography, X-Rayen_US
dc.subject.meshCysteine Endopeptidases - Chemistry - Metabolismen_US
dc.subject.meshCysteine Proteinase Inhibitors - Chemical Synthesis - Pharmacologyen_US
dc.subject.meshDrug Designen_US
dc.subject.meshHumansen_US
dc.subject.meshKineticsen_US
dc.subject.meshMiceen_US
dc.subject.meshMolecular Sequence Dataen_US
dc.subject.meshOligopeptides - Chemical Synthesis - Pharmacologyen_US
dc.subject.meshOxazoles - Chemical Synthesis - Pharmacologyen_US
dc.subject.meshProtein Conformationen_US
dc.subject.meshPyrrolidinones - Chemical Synthesis - Pharmacologyen_US
dc.subject.meshSars Virus - Enzymologyen_US
dc.subject.meshTransmissible Gastroenteritis Virus - Enzymologyen_US
dc.subject.meshTumor Cells, Cultureden_US
dc.subject.meshViral Proteins - Antagonists & Inhibitorsen_US
dc.titleDesign of wide-spectrum inhibitors targeting coronavirus main proteases.en_US
dc.typeArticleen_US
dc.identifier.emailYuen, KY:kyyuen@hkucc.hku.hken_US
dc.identifier.authorityYuen, KY=rp00366en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1371/journal.pbio.0030324-
dc.identifier.pmid16128623-
dc.identifier.scopuseid_2-s2.0-31444436972en_US
dc.identifier.volume3en_US
dc.identifier.issue10en_US
dc.identifier.spagee324en_US
dc.identifier.isiWOS:000232404600009-
dc.identifier.scopusauthoridYang, H=7406565162en_US
dc.identifier.scopusauthoridXie, W=8970936000en_US
dc.identifier.scopusauthoridXue, X=12788931200en_US
dc.identifier.scopusauthoridYang, K=8732212800en_US
dc.identifier.scopusauthoridMa, J=55210564100en_US
dc.identifier.scopusauthoridLiang, W=8970936700en_US
dc.identifier.scopusauthoridZhao, Q=7402764008en_US
dc.identifier.scopusauthoridZhou, Z=14069281700en_US
dc.identifier.scopusauthoridPei, D=7102806599en_US
dc.identifier.scopusauthoridZiebuhr, J=7003783935en_US
dc.identifier.scopusauthoridHilgenfeld, R=7006843618en_US
dc.identifier.scopusauthoridYuen, KY=36078079100en_US
dc.identifier.scopusauthoridWong, L=7402091726en_US
dc.identifier.scopusauthoridGao, G=7403167173en_US
dc.identifier.scopusauthoridChen, S=13310288700en_US
dc.identifier.scopusauthoridChen, Z=26643572800en_US
dc.identifier.scopusauthoridMa, D=7402075894en_US
dc.identifier.scopusauthoridBartlam, M=6701775559en_US
dc.identifier.scopusauthoridRao, Z=7102549060en_US

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