tetano
Editor, Senior Moderator
Antiviral Res
. 2021 Nov 18;105209.
doi: 10.1016/j.antiviral.2021.105209. Online ahead of print.
2-((1H-indol-3-yl)thio)-N-phenyl-acetamides: SARS-CoV-2 RNA-dependent RNA polymerase inhibitors
Jianyuan Zhao[SUP] 1 [/SUP], Guoning Zhang[SUP] 1 [/SUP], Yongxin Zhang[SUP] 1 [/SUP], Dongrong Yi[SUP] 1 [/SUP], Quanjie Li[SUP] 1 [/SUP], Ling Ma[SUP] 1 [/SUP], SaiSai Guo[SUP] 1 [/SUP], Xiaoyu Li[SUP] 1 [/SUP], Fei Guo[SUP] 2 [/SUP], Rongtuan Lin[SUP] 3 [/SUP], Gia Luu[SUP] 3 [/SUP], Zhenlong Liu[SUP] 4 [/SUP], Yucheng Wang[SUP] 5 [/SUP], Shan Cen[SUP] 6 [/SUP]
Affiliations
Abstract
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of Coronavirus Disease 2019 (COVID-19) pandemic. Despite intensive and global efforts to discover and develop novel antiviral therapies, only Remdesivir has been approved as a treatment for COVID-19. Therefore, effective antiviral therapeutics are still urgently needed to combat and halt the pandemic. Viral RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 demonstrates high potential as a reliable target for the development of antivirals. We previously developed a cell-based assay to assess the efficiency of compounds that target SARS-CoV-2 RdRp, as well as their tolerance to viral exoribonuclease-mediated proof-reading. In our previous study, we discovered that 2-((1H-indol-3-yl)thio)-N-phenyl-acetamides specifically targets the RdRp of both respiratory syncytial virus (RSV) and influenza A virus. Thus, we hypothesize that 2-((1H-indol-3-yl)thio)-N-phenyl-acetamides may also have the ability to inhibit SARS-CoV-2 replication by targeting its RdRp activity. In this research, we test a compound library containing 103 of 2-((1H-indol-3-yl)thio)-N-phenyl-acetamides against SARS-CoV-2 RdRp, using our cell-based assay. Among these compounds, the top five candidates strongly inhibit SARS-CoV-2 RdRp activity while exhibiting low cytotoxicity and resistance to viral exoribonuclease. Compound 6-72-2a is the most promising candidate with the lowest EC[SUB]50[/SUB] value of 1.41 μM and highest selectivity index (CC[SUB]50[/SUB]/EC[SUB]50[/SUB]) (above 70.92). Furthermore, our data suggests that 4-46b and 6-72-2a also inhibit the replication of HCoV-OC43 and HCoV-NL63 virus in a dose-dependent manner. Compounds 4-46b and 6-72-2a exhibit EC[SUB]50[/SUB] values of 1.13 μM and 0.94 μM, respectively, on HCoV-OC43 viral replication. However, higher concentrations of these compounds are needed to effectively block HCoV-NL63 replication. Together, our findings successfully identified 4-46b and 6-72-2a as promising inhibitors against SARS-CoV-2 RdRp.
Keywords: 2-((1H-indol-3-yl)thio)-N-Phenyl-acetamides; COVID-19; Nucleotide analog inhibitor; RdRp; Remdesivir; SARS-CoV-2.
. 2021 Nov 18;105209.
doi: 10.1016/j.antiviral.2021.105209. Online ahead of print.
2-((1H-indol-3-yl)thio)-N-phenyl-acetamides: SARS-CoV-2 RNA-dependent RNA polymerase inhibitors
Jianyuan Zhao[SUP] 1 [/SUP], Guoning Zhang[SUP] 1 [/SUP], Yongxin Zhang[SUP] 1 [/SUP], Dongrong Yi[SUP] 1 [/SUP], Quanjie Li[SUP] 1 [/SUP], Ling Ma[SUP] 1 [/SUP], SaiSai Guo[SUP] 1 [/SUP], Xiaoyu Li[SUP] 1 [/SUP], Fei Guo[SUP] 2 [/SUP], Rongtuan Lin[SUP] 3 [/SUP], Gia Luu[SUP] 3 [/SUP], Zhenlong Liu[SUP] 4 [/SUP], Yucheng Wang[SUP] 5 [/SUP], Shan Cen[SUP] 6 [/SUP]
Affiliations
- PMID: 34801588
- DOI: 10.1016/j.antiviral.2021.105209
Abstract
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of Coronavirus Disease 2019 (COVID-19) pandemic. Despite intensive and global efforts to discover and develop novel antiviral therapies, only Remdesivir has been approved as a treatment for COVID-19. Therefore, effective antiviral therapeutics are still urgently needed to combat and halt the pandemic. Viral RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 demonstrates high potential as a reliable target for the development of antivirals. We previously developed a cell-based assay to assess the efficiency of compounds that target SARS-CoV-2 RdRp, as well as their tolerance to viral exoribonuclease-mediated proof-reading. In our previous study, we discovered that 2-((1H-indol-3-yl)thio)-N-phenyl-acetamides specifically targets the RdRp of both respiratory syncytial virus (RSV) and influenza A virus. Thus, we hypothesize that 2-((1H-indol-3-yl)thio)-N-phenyl-acetamides may also have the ability to inhibit SARS-CoV-2 replication by targeting its RdRp activity. In this research, we test a compound library containing 103 of 2-((1H-indol-3-yl)thio)-N-phenyl-acetamides against SARS-CoV-2 RdRp, using our cell-based assay. Among these compounds, the top five candidates strongly inhibit SARS-CoV-2 RdRp activity while exhibiting low cytotoxicity and resistance to viral exoribonuclease. Compound 6-72-2a is the most promising candidate with the lowest EC[SUB]50[/SUB] value of 1.41 μM and highest selectivity index (CC[SUB]50[/SUB]/EC[SUB]50[/SUB]) (above 70.92). Furthermore, our data suggests that 4-46b and 6-72-2a also inhibit the replication of HCoV-OC43 and HCoV-NL63 virus in a dose-dependent manner. Compounds 4-46b and 6-72-2a exhibit EC[SUB]50[/SUB] values of 1.13 μM and 0.94 μM, respectively, on HCoV-OC43 viral replication. However, higher concentrations of these compounds are needed to effectively block HCoV-NL63 replication. Together, our findings successfully identified 4-46b and 6-72-2a as promising inhibitors against SARS-CoV-2 RdRp.
Keywords: 2-((1H-indol-3-yl)thio)-N-Phenyl-acetamides; COVID-19; Nucleotide analog inhibitor; RdRp; Remdesivir; SARS-CoV-2.