Interactions of Metallo-Supramolecular Nanocylinders in Biological Systems at the Subcellular Level
Information on my research for press and non-specialists can be found here.
We have designed supramolecular nanocylinders that possess markedly different structural features to conventional drugs and that should act in quite different ways at the cellular and molecular level. The synthetic agent is a tetracationic nanoscale cylinder of 2nm length and 1nm diameter. Such a structure is completely different from those of existing agents.
AFM images showing the dramatic intra-molecular DNA coiling induced by the cylinders
NMR structure of the cylinder in the major groove of DNA
We have shown in-vitro that the agent binds to both oligosaccharides and nucleic acids, with the DNA binding in particular leading to dramatic macromolecular effects; the agent induces intramolecular coiling of the DNA (acting like an artficial histone). However, the precise mode of action in cells and its cellular /molecular targets are not yet known.
My research will investigate the action of these cylinders in cells and in particular determine:
The cytotoxicity and other action of cylinders on cells. This will involve growing cells and establishing (a) effects on growth and inhibitory concentrations, (b) effects on different cell types.
Where the cylinders localise in the cells (e.g. membranes, nucleic acids…).
The nature of the interactions of the cylinders with their biomolecular targets. This will be studied using a range of biophysical techniques including absorption and fluorescence and circular and linear dichroism spectropscopies, mass spectrometry, AFM imaging, gel electrophoresis, solution and solid-state NMR
Which physiological processes are being affected. This will involve various techniques including metabalomic approaches using NMR and mass spectrometry to characterise cell metabolites.
Inherent in the project is the need to develop and draw upon a range of skills drawn from the different disciplines of Chemistry, Biology and Physics and this is reflected in the multi-disciplinary team of scientists that work together to supervise this project.
References: For further information on the design and DNA binding action of the agent see I. Meistermann, V. Moreno, M.J. Prieto, E. Moldrheim, E. Sletten, S. Khalid, P.M. Rodger, J.C. Peberdy, C.J. Isaac, A. Rodger and M.J. Hannon, Proc. Natl. Acad. Sci., USA., 2002, 99, 5069; M.J. Hannon, V. Moreno, M.J. Prieto, E. Molderheim, E. Sletten, I. Meistermann, C.J. Isaac, K.J. Sanders and A. Rodger, Angew. Chem., Intl. Ed. Engl., 2001, 40, 879; MJ Hannon and A Rodger, Pharmaceutical Visions, 2002, Autumn Issue,14-16