Identification of novel 123-triazole isatin derivatives as potent SARS-CoV-2 3CLpro inhibitors <em>via</em> click-chemistry-based rapid screening

SARS-CoV-2 3-chymotrypsin-like protease (3CLpro) is considered an attractive target for the development of anti-COVID-19 agents due to its vital function. The N-substituted isatin derivative L-26 is a potential SARS-CoV-2 3CLpro inhibitor, but it has poor cell-based antiviral activity and high cytot...

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Detalles Bibliográficos
Autores: Tollefson, Ann E., Liu, Xinyong, Zhang, Peng, Jiang, Xiangyi, Li, Jing, Viayna Gaza, Antonio, Luque Garriga, F. Xavier, Woodson, Molly, Jing, Lanlan, Gao, Shenghua, Zhao, Fabao, Xie, Minghui, Toth, Karoly, Tavis, John
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2023
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:dnet:ubarcelona__::dda3d8c54f038bca92ee1492a6ba9fee
Acceso en línea:https://hdl.handle.net/2445/229208
Access Level:acceso abierto
Palabra clave:SARS-CoV-2
COVID-19
Descripción
Sumario:SARS-CoV-2 3-chymotrypsin-like protease (3CLpro) is considered an attractive target for the development of anti-COVID-19 agents due to its vital function. The N-substituted isatin derivative L-26 is a potential SARS-CoV-2 3CLpro inhibitor, but it has poor cell-based antiviral activity and high cytotoxicity. With L-26 as the lead compound, 58 isatin derivatives were prepared using clickchemistry-based miniaturized synthesis and their 3CLpro inhibitory activities were determined by a fluorescence resonance energy transfer-based enzymatic assay. Compounds D1N8 (IC50 =0.44± 0.12 μM) and D1N52 (IC50 = 0.53 ± 0.21 μM) displayed excellent inhibitory potency against SARS-CoV-2 3CLpro, being equivalent to that of L-26 (IC50 =0.30± 0.14 μM). In addition, the cytotoxicity of D1N8 (CC50 >20 μM) and D1N52 (CC50 >20 μM) decreased significantly compared with L-26 (CC50 <2.6 μM). Further molecular dynamics simulations revealed the potential binding interactions between D1N52 and SARS-CoV-2 3CLpro. These efforts lay a solid foundation for the research of novel anti-SARS-CoV-2 agents targeting 3CLpro.

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