In-cell bioluminescence resonance energy transfer (BRET)-based assay uncovers ceritinib and CA-074 as SARS-CoV-2 papain-like protease inhibitors
Papain-like protease (PLpro) is an attractive anti-coronavirus target. The development of PLpro inhibitors, however, is hampered by the limitations of the existing PLpro assay and the scarcity of validated active compounds. We developed a novel in-cell PLpro assay based on BRET and used it to evalua...
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| Main Authors: | , , , , , , , , |
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| Format: | Book |
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Taylor & Francis Group,
2024-12-01T00:00:00Z.
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| 001 | doaj_5a01b9e861734741bbb82b9fba6c65f7 | ||
| 042 | |a dc | ||
| 100 | 1 | 0 | |a Mei Li |e author |
| 700 | 1 | 0 | |a Zhu-Chun Bei |e author |
| 700 | 1 | 0 | |a Yongtian Yuan |e author |
| 700 | 1 | 0 | |a Baogang Wang |e author |
| 700 | 1 | 0 | |a Dongna Zhang |e author |
| 700 | 1 | 0 | |a Likun Xu |e author |
| 700 | 1 | 0 | |a Liangliang Zhao |e author |
| 700 | 1 | 0 | |a Qin Xu |e author |
| 700 | 1 | 0 | |a Yabin Song |e author |
| 245 | 0 | 0 | |a In-cell bioluminescence resonance energy transfer (BRET)-based assay uncovers ceritinib and CA-074 as SARS-CoV-2 papain-like protease inhibitors |
| 260 | |b Taylor & Francis Group, |c 2024-12-01T00:00:00Z. | ||
| 500 | |a 10.1080/14756366.2024.2387417 | ||
| 500 | |a 1475-6374 | ||
| 500 | |a 1475-6366 | ||
| 520 | |a Papain-like protease (PLpro) is an attractive anti-coronavirus target. The development of PLpro inhibitors, however, is hampered by the limitations of the existing PLpro assay and the scarcity of validated active compounds. We developed a novel in-cell PLpro assay based on BRET and used it to evaluate and discover SARS-CoV-2 PLpro inhibitors. The developed assay demonstrated remarkable sensitivity for detecting the reduction of intracellular PLpro activity while presenting high reliability and performance for inhibitor evaluation and high-throughput screening. Using this assay, three protease inhibitors were identified as novel PLpro inhibitors that are structurally disparate from those previously known. Subsequent enzymatic assays and ligand-protein interaction analysis based on molecular docking revealed that ceritinib directly inhibited PLpro, showing high geometric complementarity with the substrate-binding pocket in PLpro, whereas CA-074 methyl ester underwent intracellular hydrolysis, exposing a free carboxyhydroxyl group essential for hydrogen bonding with G266 in the BL2 groove, resulting in PLpro inhibition. | ||
| 546 | |a EN | ||
| 690 | |a papain-like protease (PLpro) | ||
| 690 | |a SARS-CoV-2 | ||
| 690 | |a bioluminescence resonance energy transfer (BRET) | ||
| 690 | |a protease inhibitors | ||
| 690 | |a high-throughput screening (HTS) | ||
| 690 | |a Therapeutics. Pharmacology | ||
| 690 | |a RM1-950 | ||
| 655 | 7 | |a article |2 local | |
| 786 | 0 | |n Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 39, Iss 1 (2024) | |
| 787 | 0 | |n https://www.tandfonline.com/doi/10.1080/14756366.2024.2387417 | |
| 787 | 0 | |n https://doaj.org/toc/1475-6366 | |
| 787 | 0 | |n https://doaj.org/toc/1475-6374 | |
| 856 | 4 | 1 | |u https://doaj.org/article/5a01b9e861734741bbb82b9fba6c65f7 |z Connect to this object online. |