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Issue 20, 2021

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

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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.

Graphical abstract: Targeting structural features of viral genomes with a nano-sized supramolecular drug

Supplementary files

Article information


Submitted
15 Feb 2021
Accepted
05 Apr 2021
First published
05 Apr 2021

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2021,12, 7174-7184
Article type
Edge Article

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

L. Melidis, I. B. Styles and M. J. Hannon, Chem. Sci., 2021, 12, 7174 DOI: 10.1039/D1SC00933H

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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