tetano
Editor, Senior Moderator
Bioorg Chem
. 2023 Sep 3;140:106830.
doi: 10.1016/j.bioorg.2023.106830. Online ahead of print. Discovery of new non-covalent and covalent inhibitors targeting SARS-CoV-2 papain-like protease and main protease
Wandong Liu[SUP] 1 [/SUP], Juan Wang[SUP] 1 [/SUP], Suyun Wang[SUP] 2 [/SUP], Kairui Yue[SUP] 1 [/SUP], Yu Hu[SUP] 1 [/SUP], Xiaochun Liu[SUP] 1 [/SUP], Lihao Wang[SUP] 1 [/SUP], Shengbiao Wan[SUP] 3 [/SUP], Ximing Xu[SUP] 4 [/SUP]
Affiliations
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 EC[SUB]50[/SUB] 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.
Keywords: Covalent inhibitor; Mian protease; Non-covalent inhibitor; Papain-like protease; SARS-CoV-2.
. 2023 Sep 3;140:106830.
doi: 10.1016/j.bioorg.2023.106830. Online ahead of print. Discovery of new non-covalent and covalent inhibitors targeting SARS-CoV-2 papain-like protease and main protease
Wandong Liu[SUP] 1 [/SUP], Juan Wang[SUP] 1 [/SUP], Suyun Wang[SUP] 2 [/SUP], Kairui Yue[SUP] 1 [/SUP], Yu Hu[SUP] 1 [/SUP], Xiaochun Liu[SUP] 1 [/SUP], Lihao Wang[SUP] 1 [/SUP], Shengbiao Wan[SUP] 3 [/SUP], Ximing Xu[SUP] 4 [/SUP]
Affiliations
- PMID: 37683544
- DOI: 10.1016/j.bioorg.2023.106830
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 EC[SUB]50[/SUB] 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.
Keywords: Covalent inhibitor; Mian protease; Non-covalent inhibitor; Papain-like protease; SARS-CoV-2.