Discovery of new non-covalent and covalent inhibitors targeting SARS-CoV-2 papain-like protease and main protease
Copyright © 2023 Elsevier Inc. All rights reserved..
Global coronavirus disease 2019 (COVID-19) pandemic still threatens human health and public safety, and the development of effective antiviral agent is urgently needed. The SARS-CoV-2 main protease (Mpro) and papain-like protease (PLpro) are vital proteins in viral replication and promising therapeutic targets. Additionally, PLpro also modulates host immune response by cleaving ubiquitin and interferon-stimulated gene product 15 (ISG15) from ISGylated host proteins. In this report, we identified [1,2]selenazolo[5,4-c]pyridin-3(2H)-one and benzo[d]isothiazol-3(2H)-one as attractive scaffolds of PLpro and Mpro inhibitors. The representative compounds 6c and 7e exhibited excellent PLpro inhibition with percent inhibition of 42.9% and 44.9% at 50 nM, respectively. The preliminary enzyme kinetics experiment and fluorescent labelling experiment results determined that 6c was identified as a covalent PLpro inhibitor, while 7e was a non-covalent inhibitor. Molecular docking and dynamics simulations revealed that 6c and 7e bound to Zn-finger domain of PLpro. Compounds 6c and 7e were also identified to potent Mpro inhibitors, and they exhibited potent antiviral activities in SARS-CoV-2 infected Vero E6 cells, with EC50 value of 3.9 μM and 7.4 μM, respectively. In addition, the rat liver homogenate half-life of 6c and 7e exceeded 24 h. These findings suggest that 6c and 7e are promising led compounds for further development of PLpro/Mpro dual-target antiviral drugs.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:140 |
|---|---|
| Enthalten in: |
Bioorganic chemistry - 140(2023) vom: 15. Nov., Seite 106830 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Liu, Wandong [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 18.09.2023 Date Revised 18.09.2023 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.bioorg.2023.106830 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM361810695 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM361810695 | ||
| 003 | DE-627 | ||
| 005 | 20231226085925.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.bioorg.2023.106830 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1205.xml |
| 035 | |a (DE-627)NLM361810695 | ||
| 035 | |a (NLM)37683544 | ||
| 035 | |a (PII)S0045-2068(23)00491-1 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Liu, Wandong |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Discovery of new non-covalent and covalent inhibitors targeting SARS-CoV-2 papain-like protease and main protease |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 18.09.2023 | ||
| 500 | |a Date Revised 18.09.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Elsevier Inc. All rights reserved. | ||
| 520 | |a Global coronavirus disease 2019 (COVID-19) pandemic still threatens human health and public safety, and the development of effective antiviral agent is urgently needed. The SARS-CoV-2 main protease (Mpro) and papain-like protease (PLpro) are vital proteins in viral replication and promising therapeutic targets. Additionally, PLpro also modulates host immune response by cleaving ubiquitin and interferon-stimulated gene product 15 (ISG15) from ISGylated host proteins. In this report, we identified [1,2]selenazolo[5,4-c]pyridin-3(2H)-one and benzo[d]isothiazol-3(2H)-one as attractive scaffolds of PLpro and Mpro inhibitors. The representative compounds 6c and 7e exhibited excellent PLpro inhibition with percent inhibition of 42.9% and 44.9% at 50 nM, respectively. The preliminary enzyme kinetics experiment and fluorescent labelling experiment results determined that 6c was identified as a covalent PLpro inhibitor, while 7e was a non-covalent inhibitor. Molecular docking and dynamics simulations revealed that 6c and 7e bound to Zn-finger domain of PLpro. Compounds 6c and 7e were also identified to potent Mpro inhibitors, and they exhibited potent antiviral activities in SARS-CoV-2 infected Vero E6 cells, with EC50 value of 3.9 μM and 7.4 μM, respectively. In addition, the rat liver homogenate half-life of 6c and 7e exceeded 24 h. These findings suggest that 6c and 7e are promising led compounds for further development of PLpro/Mpro dual-target antiviral drugs | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Covalent inhibitor | |
| 650 | 4 | |a Mian protease | |
| 650 | 4 | |a Non-covalent inhibitor | |
| 650 | 4 | |a Papain-like protease | |
| 650 | 4 | |a SARS-CoV-2 | |
| 650 | 7 | |a Antiviral Agents |2 NLM | |
| 650 | 7 | |a Coloring Agents |2 NLM | |
| 650 | 7 | |a Endopeptidases |2 NLM | |
| 650 | 7 | |a EC 3.4.- |2 NLM | |
| 650 | 7 | |a papain-like protease, SARS-CoV-2 |2 NLM | |
| 650 | 7 | |a EC 3.4.22.2 |2 NLM | |
| 650 | 7 | |a Peptide Hydrolases |2 NLM | |
| 650 | 7 | |a EC 3.4.- |2 NLM | |
| 650 | 7 | |a Coronavirus Protease Inhibitors |2 NLM | |
| 650 | 7 | |a Coronavirus Papain-Like Proteases |2 NLM | |
| 650 | 7 | |a EC 3.4.22.2 |2 NLM | |
| 650 | 7 | |a 3C-like proteinase, SARS-CoV-2 |2 NLM | |
| 650 | 7 | |a EC 3.4.22.- |2 NLM | |
| 700 | 1 | |a Wang, Juan |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Suyun |e verfasserin |4 aut | |
| 700 | 1 | |a Yue, Kairui |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Xiaochun |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Lihao |e verfasserin |4 aut | |
| 700 | 1 | |a Wan, Shengbiao |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Ximing |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Bioorganic chemistry |d 1986 |g 140(2023) vom: 15. Nov., Seite 106830 |w (DE-627)NLM012846570 |x 1090-2120 |7 nnns |
| 773 | 1 | 8 | |g volume:140 |g year:2023 |g day:15 |g month:11 |g pages:106830 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.bioorg.2023.106830 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 140 |j 2023 |b 15 |c 11 |h 106830 | ||