Workflow to Identify Antiviral Molecules Targeting Genomic Structures of SARS-CoV-2


Workflow to Identify Antiviral Molecules Targeting Genomic Structures of SARS-CoV-2


L Pavanello1
1 LifeArc, UK


RNA viruses such as coronaviruses share a translation regulation mechanism called ‘Programmed -1 Ribosomal Frameshifting’ (-1 PRF) to finely tune the expression balance of ORFs essential for infection, that are encoded in different frames. To activate -1 PRF, ribosomes are stalled on the RNA genome by a pseudoknot secondary structure element, that works in concert with a slippery site and an upstream attenuator hairpin; when stalled, ribosomes may shift back by one nucleotide and resume translation on a different reading frame. Recently published data confirmed that the activity of -1 PRF in SARS-CoV-2 can be modulated with molecules targeting the pseudoknot. This program aims to develop novel antiviral molecules targeting the SARS-CoV-2 pseudoknot. Our approach comprises an AS-MS screen to identify small molecule binders to the pseudoknot. Hits are confirmed, profiled and optimised using an array of biophysical assays (SPR, MST, NMR) and functional activity assayed in in vitro reporter assays before testing for antiviral activity in cell-based infection models. Ultimately, the identified small molecules will have to demonstrate in vivo efficacy in infection models of SARS-CoV-2. However, since the -1 PRF mechanism is common in many RNA viruses, this workflow may be more broadly applicable to future outbreaks.

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