tetano
Editor, Senior Moderator
Biochem J
. 2021 Jul 16;478(13):2405-2423.
doi: 10.1042/BCJ20210201.
Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp13 helicase
Jingkun Zeng[SUP] #[/SUP][SUP] 1 [/SUP], Florian Weissmann[SUP] #[/SUP][SUP] 1 [/SUP], Agustina P Bertolin[SUP] #[/SUP][SUP] 1 [/SUP], Viktor Posse[SUP] 1 [/SUP], Berta Canal[SUP] 1 [/SUP], Rachel Ulferts[SUP] 2 [/SUP], Mary Wu[SUP] 3 [/SUP], Ruth Harvey[SUP] 4 [/SUP], Saira Hussain[SUP] 4 [/SUP], Jennifer C Milligan[SUP] 1 [/SUP], Chloe Roustan[SUP] 5 [/SUP], Annabel Borg[SUP] 5 [/SUP], Laura McCoy[SUP] 6 [/SUP], Lucy S Drury[SUP] 1 [/SUP], Svend Kjaer[SUP] 5 [/SUP], John McCauley[SUP] 4 [/SUP], Michael Howell[SUP] 3 [/SUP], Rupert Beale[SUP] 2 [/SUP], John F X Diffley[SUP] 1 [/SUP]
Affiliations
Abstract
The coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global public health challenge. While the efficacy of vaccines against emerging and future virus variants remains unclear, there is a need for therapeutics. Repurposing existing drugs represents a promising and potentially rapid opportunity to find novel antivirals against SARS-CoV-2. The virus encodes at least nine enzymatic activities that are potential drug targets. Here, we have expressed, purified and developed enzymatic assays for SARS-CoV-2 nsp13 helicase, a viral replication protein that is essential for the coronavirus life cycle. We screened a custom chemical library of over 5000 previously characterized pharmaceuticals for nsp13 inhibitors using a fluorescence resonance energy transfer-based high-throughput screening approach. From this, we have identified FPA-124 and several suramin-related compounds as novel inhibitors of nsp13 helicase activity in vitro. We describe the efficacy of these drugs using assays we developed to monitor SARS-CoV-2 growth in Vero E6 cells.
Keywords: COVID-19; RNA helicase; coronavirus; nsp13.
. 2021 Jul 16;478(13):2405-2423.
doi: 10.1042/BCJ20210201.
Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp13 helicase
Jingkun Zeng[SUP] #[/SUP][SUP] 1 [/SUP], Florian Weissmann[SUP] #[/SUP][SUP] 1 [/SUP], Agustina P Bertolin[SUP] #[/SUP][SUP] 1 [/SUP], Viktor Posse[SUP] 1 [/SUP], Berta Canal[SUP] 1 [/SUP], Rachel Ulferts[SUP] 2 [/SUP], Mary Wu[SUP] 3 [/SUP], Ruth Harvey[SUP] 4 [/SUP], Saira Hussain[SUP] 4 [/SUP], Jennifer C Milligan[SUP] 1 [/SUP], Chloe Roustan[SUP] 5 [/SUP], Annabel Borg[SUP] 5 [/SUP], Laura McCoy[SUP] 6 [/SUP], Lucy S Drury[SUP] 1 [/SUP], Svend Kjaer[SUP] 5 [/SUP], John McCauley[SUP] 4 [/SUP], Michael Howell[SUP] 3 [/SUP], Rupert Beale[SUP] 2 [/SUP], John F X Diffley[SUP] 1 [/SUP]
Affiliations
- PMID: 34198322
- DOI: 10.1042/BCJ20210201
Abstract
The coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global public health challenge. While the efficacy of vaccines against emerging and future virus variants remains unclear, there is a need for therapeutics. Repurposing existing drugs represents a promising and potentially rapid opportunity to find novel antivirals against SARS-CoV-2. The virus encodes at least nine enzymatic activities that are potential drug targets. Here, we have expressed, purified and developed enzymatic assays for SARS-CoV-2 nsp13 helicase, a viral replication protein that is essential for the coronavirus life cycle. We screened a custom chemical library of over 5000 previously characterized pharmaceuticals for nsp13 inhibitors using a fluorescence resonance energy transfer-based high-throughput screening approach. From this, we have identified FPA-124 and several suramin-related compounds as novel inhibitors of nsp13 helicase activity in vitro. We describe the efficacy of these drugs using assays we developed to monitor SARS-CoV-2 growth in Vero E6 cells.
Keywords: COVID-19; RNA helicase; coronavirus; nsp13.