Targeting structural features of viral genomes with a nano-sized supramolecular drug.

Lazaros Melidis,Michael J Hannon,Iain B Styles

doi:10.1039/d1sc00933h

Lazaros Melidis, Michael J Hannon + Show 1 more

Open Access

https://doi.org/10.1039/d1sc00933h

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Abstract

RNA targeting is an exciting frontier for drug design. Intriguing targets include functional RNA structures in structurally-conserved untranslated regions (UTRs) of many lethal viruses. However, computational docking screens, valuable in protein structure targeting, fail for inherently flexible RNA. Herein we harness MD simulations with Markov state modeling to enable nanosize metallo-supramolecular cylinders to explore the dynamic RNA conformational landscape of HIV-1 TAR untranslated region RNA (representative for many viruses) replicating experimental observations. These cylinders are exciting as they have unprecedented nucleic acid binding and are the first supramolecular helicates shown to have anti-viral activity in cellulo: the approach developed in this study provides additional new insight about how such viral UTR structures might be targeted with the cylinder binding into the heart of an RNA-bulge cavity, how that reduces the conformational flexibility of the RNA and molecular details of the insertion mechanism. The approach and understanding developed represents a new roadmap for design of supramolecular drugs to target RNA structural motifs across biology and nucleic acid nanoscience.

Highlights

Infectious disease represents one of the greatest current threats to humans as demonstrated by the frequency of recent lethal viral outbreaks: 4 out of the 10 greatest threats identi ed by the World Health Organization are viral related
These cylinders are exciting as they have unprecedented nucleic acid binding and are the first supramolecular helicates shown to have anti-viral activity in cellulo: the approach developed in this study provides additional new insight about how such viral untranslated regions (UTRs) structures might be targeted with the cylinder binding into the heart of an RNAbulge cavity, how that reduces the conformational flexibility of the RNA and molecular details of the insertion mechanism
To identify the best features to apply the work ow to, we explored a variety of potential different features to see which best captured the kinetic variance that occurred during the simulations: 1. Position of centre of mass (COM) of each residue is a low dimensional and relatively efficient way to capture different states, including simulations that involve one or more cylinders

Summary

Introduction

Infectious disease represents one of the greatest current threats to humans as demonstrated by the frequency of recent lethal viral outbreaks: 4 out of the 10 greatest threats identi ed by the World Health Organization are viral related. To target broad classes of disease, drugs that target the nucleic acids[1,2,3,4,5] (DNA, RNA) of the infectious agents are of particular interest with RNA increasingly recognized as a druggable target.[6,7] The rapid emergence of infections, and subsequent rapid evolution of viral genetic sequences, means that drugs that target a speci c sequence are unsuitable. Similar bulges are found in UTRs of other RNA viruses including coronaviruses and SARS-COV-2. These UTR structures represent exciting potential anti-viral targets

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