Biochem J . Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp13 helicase

[tetano]

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 ^{# 1} , Florian Weissmann ^{# 1} , Agustina P Bertolin ^{# 1} , Viktor Posse ¹ , Berta Canal ¹ , Rachel Ulferts ² , Mary Wu ³ , Ruth Harvey ⁴ , Saira Hussain ⁴ , Jennifer C Milligan ¹ , Chloe Roustan ⁵ , Annabel Borg ⁵ , Laura McCoy ⁶ , Lucy S Drury ¹ , Svend Kjaer ⁵ , John McCauley ⁴ , Michael Howell ³ , Rupert Beale ² , John F X Diffley ¹



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.