Exploring the Druggability of Conserved RNA Regulatory Elements in the SARS‐CoV‐2 Genome

Abstract

SARS‐CoV‐2 contains a positive single‐stranded RNA genome of approximately 30 000 nucleotides. Within this genome, 15 RNA elements were identified as conserved between SARS‐CoV and SARS‐CoV‐2. By nuclear magnetic resonance (NMR) spectroscopy, we previously determined that these elements fold independently, in line with data from in vivo and ex‐vivo structural probing experiments. These elements contain non‐base‐paired regions that potentially harbor ligand‐binding pockets. Here, we performed an NMR‐based screening of a poised fragment library of 768 compounds for binding to these RNAs, employing three different 1H‐based 1D NMR binding assays. The screening identified common as well as RNA‐element specific hits. The results allow selection of the most promising of the 15 RNA elements as putative drug targets. Based on the identified hits, we derive key functional units and groups in ligands for effective targeting of the RNA of SARS‐CoV‐2.

AI-Generated Virtual Libraries Could Help Uncover RNA-Specific Regions of Chemical Space

“…Rings with red boxes are those found recently reported library of molecules that were validated to bind to various RNA elements within the SARS-CoV-2 genome. 15 (b) Relative frequency of top 40 ring systems found in our combined virtual library. For comparison, the relative frequency in a combined library targeting CDK2 and M Pro .…”

“…Highlighted in red are ring systems among the top 40 that are present in validated binders of various RNA elements within the SARS-CoV-2 genome. 15…”

“…Here we show ring systems observed in at least ten unique molecules. Rings with red boxes are those found recently reported library of molecules that were validated to bind to various RNA elements within the SARS-CoV-2 genome 15. (b) Relative frequency of top 40 ring systems found in our combined virtual library.…”

“…For comparison, the relative frequency in a combined library targeting CDK2 and M Pro . Highlighted in red are ring systems among the top 40 that are present in validated binders of various RNA elements within the SARS-CoV-2 genome 15.…”

“…We show ring systems that we observe in at least ten unique molecules. Rings with red boxes are those found recently reported library of molecules that were validated to bind to various RNA elements within the SARS-CoV-2 genome 15.…”