Principal Supervisor: Prof Mike Hannon Link opens in a new window(Chemistry)

Co-supervisor: Prof Teresa CarlomagnoLink opens in a new window (Biosciences & Henry Wellcome NMR Centre)

PhD project title: Structural characterisation of regulatory viral RNA structures bound to supramolecular drugs

University of Registration: University of Birmingham

Project outline:

RNA structure targeting is a new frontier for molecular design. In particular there are a range of functional RNA structures found in structurally-conserved untranslated regions (UTRs) of many viruses and these are intriguing targets. These UTRs are not only highly structured but often share common structural elements that are functionally essential and so conserved as the virus evolves (drifts) genetically. In RNA viruses, such as HIVs, coronaviruses, dengue and zika, functional involvement of the UTR has been shown in either initiation of replication (for example by recruiting proteins or by direct interaction with the ribosome) or regulation of the replication cycle. This project will explore new agents that bind these functional structures and explore the effect of binding on their structure and dynamics. By binding and interfering with them, and then studying the effects, we will learn more about the role of these structures in viral infection.

We have previously shown that nanoscale metallo-supramolecular cylinders are unique nano-drug that can bind within RNA cavities (see Figure) (1, 3, 4). These cylinders bind bulge structures in the RNA of both HIV and SARS-CoV-2 viral genome and prevent their replication in cells (1,3,4).

In this project we will use our world-leading expertise in high-field NMR determinations of RNA structures (2) to get unique insight into the binding events and their structural effects. We will combine the NMR experimental data with molecular dynamics simulations. The work will be guided by experimental RNA SHAPE assessment of binding to longer RNA sequences to identify the sites of the binding preference which are then interrogated in detail. Chemical synthesis and design will be used to prepare the new binding agents, which will be fully characterised using a range of analytical techniques.

The approach and understanding developed will represent a new roadmap for design of drugs to target RNA structural motifs across biology and nucleic acid nanoscience, that can allow us to probe the role of such structures in viral infection.

References:

1 Supramolecular cylinders target bulge structures in the 5’ UTR of the RNA genome of SARS-CoV-2 and inhibit viral replication. L. Melidis, H.J. Hill, N.J. Coltman, S.P. Davies, K. Winczura, T. Chauhan, J.S. Craig, A. Garai, C.A.J. Hooper, R.T. Egan, J.A. McKeating, N.J. Hodges, Z. Stamataki, P. Grzechnik, M.J. Hannon, Angew. Chem. Int. Ed., 2021, 60, 18144-51. doi: 10.1002/anie.202104179 BioRXive doi: 10.1101/2021.03.30.437757

2.Solid-state NMR Spectroscopy of RNA. A Marchanka & T Carlomagno, Methods in Enzymology, 2019, 615, 333–371

3 Targeting structural features of viral genomes with a nano-sized supramolecular drug. L. Melidis, I.B. Styles, M.J. Hannon, Chem. Sci., 2021, 12, 7174-84. doi: 10.1039/D1SC00933H

4 Metallo supramolecular cylinders inhibit HIV-1 TAR-TAT complex formation and viral replication in cellulo. L. Cardo, I. Nawroth, P.J. Cail, J.A. McKeating, M. J. Hannon, Scientific Reports, 2018, 8, Article number 13342. DOI: 10.1038/s41598-018-31513-3.

 

BBSRC Strategic Research Priority: Understanding the rules of life – Structural Biology

 

Techniques that will be undertaken during the project:

High field NMR structure studies

Molecular Dynamics simulations on viral RNA structures and drugs that recognise them

Molecular probe design and chemical synthesis

Compound characterisation

RNA binding studies using spectroscopies and gels
 

Contact: Prof Mike Hannon Link opens in a new window