tetano
Editor, Senior Moderator
Eur J Med Chem
. 2024 Jun 25:275:116629.
doi: 10.1016/j.ejmech.2024.116629. Online ahead of print. Development of novel antivrial agents that induce the degradation of the main protease of human-infecting coronaviruses
Shuihong Cheng[SUP] 1 [/SUP], Yong Feng[SUP] 2 [/SUP], Wei Li[SUP] 3 [/SUP], Tong Liu[SUP] 4 [/SUP], Xun Lv[SUP] 4 [/SUP], Xiaomei Tong[SUP] 2 [/SUP], Gan Xi[SUP] 4 [/SUP], Xin Ye[SUP] 2 [/SUP], Xuebing Li[SUP] 5 [/SUP]
Affiliations
The family of human-infecting coronaviruses (HCoVs) poses a serious threat to global health and includes several highly pathogenic strains that cause severe respiratory illnesses. It is essential that we develop effective broad-spectrum anti-HCoV agents to prepare for future outbreaks. In this study, we used PROteolysis TArgeting Chimera (PROTAC) technology focused on degradation of the HCoV main protease (M[SUP]pro[/SUP]), a conserved enzyme essential for viral replication and pathogenicity. By adapting the M[SUP]pro[/SUP] inhibitor GC376, we produced two novel PROTACs, P2 and P3, which showed relatively broad-spectrum activity against the human-infecting CoVs HCoV-229E, HCoV-OC43, and SARS-CoV-2. The concentrations of these PROTACs that reduced virus replication by 50 % ranged from 0.71 to 4.6 μM, and neither showed cytotoxicity at 100 μM. Furthermore, mechanistic binding studies demonstrated that P2 and P3 effectively targeted HCoV-229E, HCoV-OC43, and SARS-CoV-2 by degrading M[SUP]pro[/SUP] within cells in vitro. This study highlights the potential of PROTAC technology in the development of broad-spectrum anti-HCoVs agents, presenting a novel approach for dealing with future viral outbreaks, particularly those stemming from CoVs.
Keywords: Broad-spectrum; Degradation; Main protease; PROTAC; anti-HCoV agents.
. 2024 Jun 25:275:116629.
doi: 10.1016/j.ejmech.2024.116629. Online ahead of print. Development of novel antivrial agents that induce the degradation of the main protease of human-infecting coronaviruses
Shuihong Cheng[SUP] 1 [/SUP], Yong Feng[SUP] 2 [/SUP], Wei Li[SUP] 3 [/SUP], Tong Liu[SUP] 4 [/SUP], Xun Lv[SUP] 4 [/SUP], Xiaomei Tong[SUP] 2 [/SUP], Gan Xi[SUP] 4 [/SUP], Xin Ye[SUP] 2 [/SUP], Xuebing Li[SUP] 5 [/SUP]
Affiliations
- PMID: 38941718
- DOI: 10.1016/j.ejmech.2024.116629
The family of human-infecting coronaviruses (HCoVs) poses a serious threat to global health and includes several highly pathogenic strains that cause severe respiratory illnesses. It is essential that we develop effective broad-spectrum anti-HCoV agents to prepare for future outbreaks. In this study, we used PROteolysis TArgeting Chimera (PROTAC) technology focused on degradation of the HCoV main protease (M[SUP]pro[/SUP]), a conserved enzyme essential for viral replication and pathogenicity. By adapting the M[SUP]pro[/SUP] inhibitor GC376, we produced two novel PROTACs, P2 and P3, which showed relatively broad-spectrum activity against the human-infecting CoVs HCoV-229E, HCoV-OC43, and SARS-CoV-2. The concentrations of these PROTACs that reduced virus replication by 50 % ranged from 0.71 to 4.6 μM, and neither showed cytotoxicity at 100 μM. Furthermore, mechanistic binding studies demonstrated that P2 and P3 effectively targeted HCoV-229E, HCoV-OC43, and SARS-CoV-2 by degrading M[SUP]pro[/SUP] within cells in vitro. This study highlights the potential of PROTAC technology in the development of broad-spectrum anti-HCoVs agents, presenting a novel approach for dealing with future viral outbreaks, particularly those stemming from CoVs.
Keywords: Broad-spectrum; Degradation; Main protease; PROTAC; anti-HCoV agents.