Supramolecular Cylinders Target Bulge Structures in the 5' UTR of the RNA Genome of SARS-CoV-2 and Inhibit Viral Replication*.

Lazaros Melidis,Scott P Davies,Michael J Hannon,Aditya Garai,Ross T Egan,Kinga Winczura,Catherine A J Hooper,Jane A Mckeating,Pawel Grzechnik,Nikolas J Hodges,Zania Stamataki,Tasha Chauhan,James S Craig,Nicholas J Coltman,Harriet J Hill

doi:10.1002/anie.202104179

Abstract

The untranslated regions (UTRs) of viral genomes contain a variety of conserved yet dynamic structures crucial for viral replication, providing drug targets for the development of broad spectrum anti‐virals. We combine in vitro RNA analysis with molecular dynamics simulations to build the first 3D models of the structure and dynamics of key regions of the 5′ UTR of the SARS‐CoV‐2 genome. Furthermore, we determine the binding of metallo‐supramolecular helicates (cylinders) to this RNA structure. These nano‐size agents are uniquely able to thread through RNA junctions and we identify their binding to a 3‐base bulge and the central cross 4‐way junction located in stem loop 5. Finally, we show these RNA‐binding cylinders suppress SARS‐CoV‐2 replication, highlighting their potential as novel anti‐viral agents.

Highlights

SARS-CoV-2 is a novel coronavirus that causes COVID19 and as of 1st March 2021 there have been 113 267 303 recorded cases and 2 520 550 deaths worldwide.[1]
To create a 3D dynamic model of the 5’ untranslated regions (UTRs) from the published genome sequence[38], our approach was to predict the secondary structures in silico, obtain experimental evidence to verify these structures, and model the tertiary structure and its dynamic behavior, again with experimental validation
We have shown that by combining experimental SHAPE results with molecular dynamics simulations we can create 3D models of the structure and dynamics of key individual stems that make up the 5’ UTR of SARS-CoV-2

Summary

Introduction

SARS-CoV-2 is a novel coronavirus that causes COVID19 and as of 1st March 2021 there have been 113 267 303 recorded cases and 2 520 550 deaths worldwide.[1]. We have characterized the binding of cylinders in an RNA 3-way junction[32] by crystallography (Figure 1 c) and showed analogous binding in an RNA bulge structure.[33,34] we demonstrated cylinder binding to an RNA 3-base bulge in the TAR region of the HIV-1 genome (located in its UTR), that prevented HIV-1 replication.[34] Given this anti-viral activity against HIV-1, we were interested to assess whether these cylinders would bind structures in the UTR of SARS-CoV-2. We show that cylinders inhibit SARS-CoV-2 viral replication in cells

Results and Discussion

Conclusion

Conflict of interest