Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp13 helicase.
Jingkun ZengFlorian WeissmannAgustina P BertolinViktor PosseBerta CanalRachel UlfertsMary WuRuth HarveySaira HussainJennifer C MilliganChloe RoustanAnnabel BorgLaura McCoyLucy S DrurySvend KjaerJohn McCauleyMichael HowellRupert BealeJohn F X DiffleyPublished in: The Biochemical journal (2021)
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.
Keyphrases
- sars cov
- respiratory syndrome coronavirus
- energy transfer
- small molecule
- coronavirus disease
- public health
- life cycle
- hydrogen peroxide
- high throughput
- quantum dots
- protein protein
- drug induced
- emergency department
- nitric oxide
- signaling pathway
- climate change
- dna methylation
- cell proliferation
- genome wide
- current status
- pi k akt
- human health
- disease virus
- adverse drug