Targeting the SARS-CoV‑2 RNA Translation Initiation Element SL1 by Molecules of Low Molecular Weight

TL;DR

This paper describes the development of small molecules that inhibit SARS-CoV-2 RNA translation by targeting a key RNA structure called SL1.

Contribution

The study introduces a novel NMR-guided approach to design low molecular weight inhibitors targeting the SARS-CoV-2 SL1 RNA element.

Findings

Two compounds, A.2 and A.13, showed significant and selective inhibition of SL1 in a cell-free translation assay.

NMR spectroscopy was used effectively to guide fragment derivatization and optimize binding affinity and specificity.

The study highlights the potential of targeting viral RNA structures for antiviral drug development.

Abstract

We present the development of low molecular weight inhibitors
that
target the 5′-terminal RNA stem-loop 1 (SL1) of the SARS-CoV-2
genome. SL1 is crucial for allowing viral protein synthesis in the
context of global translational repression in infected cells. We applied
compound- and RNA-detected nuclear magnetic resonance spectroscopy
(NMR) experiments to guide a fragment-growth strategy based on two
primary NMR screening hits from a diverse fragment library poised
for follow-up chemistry. These primary hits with molecular weights
of around 200 Da were derivatized with the aim of improving the initial
solubility, binding affinity, and target specificity. We used NMR
to monitor solubility changes, binding affinity, and specific binding
to the SL1 binding pocket during the fragment derivatization campaign.
Compounds scoring the best in all three categories were further tested
for their inhibitory effect on SL1 in a cell-free translation assay,
where the best two compounds, A.2 and A.13, showed both significant
and selective inhibition. Our results demonstrate that small molecules
targeting translation initiation of SARS-CoV-2 can be rapidly obtained
using NMR-guided medicinal chemistry, and that the correlation between
affinity, selectivity, and in situ function of the derived compounds
is still to be explored.

Figures