Lecture

MCBIM Lecture: Supramolecular Recognition of DNA and RNA Junction Structures for Anti-viral and Anti-cancer Therapy

• Prof. Mike Hannon (University of Birmingham, UK)

Date

Tuesday 27 February 2024

Time

10:00 - 11:00

Location

Gorlaeus Building
Einsteinweg 55
2333 CC Leiden

Room

DM.0.13

Abstract

Metallo-supramolecular cylinders (helicates) bind strongly to DNA and RNA Y-shaped junctions, forks and bulges, and prevent DNA transactions. They enter cells and rapidly localise in cell nuclei, where the fork-binding agents interfere with the processing of DNA leading to cell cycle arrest followed by apoptosis, without inducing genotoxicity or mutagenicity.[1] As a route to control the activity of these agents, we encapsulate them in a curcubituril ring to create a rotaxane structure, with release from the rotaxane switching on the junction-binding activity.[2] We also extended our junction recognition approach to organometallic agents that recognise the cavities of DNA 4-way Holliday junctions.[3]

Recognition of a specific nucleic acid shape is a powerful approach: In RNA-viruses the ends of the genome are non-coding parts which fold into specific structures and regulate viral replication. The same structures are common to many different viruses and an exciting new anti-viral target.  We have shown that some of our agents can bind junction and bulge structures (Fig 1) in the untranslated regions of both SARS-CoV-2 and HIV-1 and show potent anti-viral activities at concentration levels where they are not cytotoxic to mammalian cells.[4]

References

1. L. Cardo, M.J. Hannon, Metal Ions Life Sci., 2018, 18, 303-324.
2. C.A.J. Hooper, L. Cardo, J.S. Craig, L. Melidis, A. Garai, R.T. Egan, V. Sadovnikova, F. Burkert, L. Male, N.J. Hodges, D.F. Browning, R. Rosas, F. Liu, F.V. Rocha, M.A. Lima, S.Liu, D. Bardelang, M.J. Hannon, J. Am. Chem. Soc., 2020, 142, 20651–20660.
3. J.S. Craig, L. Melidis, H.D. Williams, S.J. Dettmer, A.A. Heidecker, P.J. Altmann, S. Guan, C. Campbell, D.F. Browning, R.K.O. Sigel, S. Johannsen, R.T. Egan, B. Aikman, A. Casini, A. Pöthig, M.J. Hannon, J. Am. Chem. Soc., 2023, 145, 13570.
4. 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; L. Melidis, I.B. Styles, M.J. Hannon, Chem. Sci., 2021, 12, 7174-7184.