Identification of Darunavir Derivatives for Inhibition of SARS-CoV-2 3CLpro
The effective antiviral agents that treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently needed around the world. The 3C-like protease (3CLpro) of SARS-CoV-2 plays a pivotal role in virus replication; it also has become an important therapeutic target for the infection of SARS-CoV-2. In this work, we have identified Darunavir derivatives that inhibit the 3CLpro through a high-throughput screening method based on a fluorescence resonance energy transfer (FRET) assay in vitro. We found that the compounds 29# and 50# containing polyphenol and caffeine derivatives as the P2 ligand, respectively, exhibited favorable anti-3CLpro potency with EC50 values of 6.3 μM and 3.5 μM and were shown to bind to SARS-CoV-2 3CLpro in vitro. Moreover, we analyzed the binding mode of the DRV in the 3CLpro through molecular docking. Importantly, 29# and 50# exhibited a similar activity against the protease in Omicron variants. The inhibitory effect of compounds 29# and 50# on the SARS-CoV-2 3CLpro warrants that they are worth being the template to design functionally improved inhibitors for the treatment of COVID-19.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:23 |
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| Enthalten in: |
International journal of molecular sciences - 23(2022), 24 vom: 16. Dez. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ma, Ling [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 04.01.2023 Date Revised 04.01.2023 published: Electronic Citation Status MEDLINE |
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| doi: |
10.3390/ijms232416011 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM350671737 |
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| 520 | |a The effective antiviral agents that treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently needed around the world. The 3C-like protease (3CLpro) of SARS-CoV-2 plays a pivotal role in virus replication; it also has become an important therapeutic target for the infection of SARS-CoV-2. In this work, we have identified Darunavir derivatives that inhibit the 3CLpro through a high-throughput screening method based on a fluorescence resonance energy transfer (FRET) assay in vitro. We found that the compounds 29# and 50# containing polyphenol and caffeine derivatives as the P2 ligand, respectively, exhibited favorable anti-3CLpro potency with EC50 values of 6.3 μM and 3.5 μM and were shown to bind to SARS-CoV-2 3CLpro in vitro. Moreover, we analyzed the binding mode of the DRV in the 3CLpro through molecular docking. Importantly, 29# and 50# exhibited a similar activity against the protease in Omicron variants. The inhibitory effect of compounds 29# and 50# on the SARS-CoV-2 3CLpro warrants that they are worth being the template to design functionally improved inhibitors for the treatment of COVID-19 | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Xie, Yongli |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Mei |e verfasserin |4 aut | |
| 700 | 1 | |a Yi, Dongrong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Jianyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Saisai |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yongxin |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Quanjie |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yucheng |e verfasserin |4 aut | |
| 700 | 1 | |a Cen, Shan |e verfasserin |4 aut | |
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