Metal Complexes as Inhibitors of Protein-Protein Interactions
Lead Research Organisation:
Queen's University Belfast
Department Name: Sch of Chemistry and Chemical Eng
Abstract
Although many cellular processes depend upon enzymatic reactions, protein-protein interactions populate a significant number of regulatory pathways - thus an explosion of interest in their study mirrors a pivotal role in diseased states. In order to manipulate effectively biological systems, there is a pressing need for small molecules that inhibit these interactions through strong and selective recognition of the interacting surfaces. The internal 'lock and key' type enzyme-substrate molecular recognition model has led to a good understanding of how to design small molecule inhibitors. However, it is not clear how the external 'hand gripping a ball' type recognition that occurs in protein-protein interactions, can be replicated using small molecules. Protein-protein interactions involve complementary large shapeless surfaces with multiple non-covalent contacts. In this work we will use small, easy to make, building-blocks that can be brought together using either a template directed synthesis, or self-organisation, to make 'protein surface mimics'; molecular entities that posses the molecular information necessary to recognise a protein surface and block the interaction it makes with its partner. Template directed synthesis and self-assembly are methods of synthesis used to assemble complex architectures from smaller components. They use the information within the components as an instruction set for the construction of the complex architecture. Methods that can do this are essential to the development of new strategies to understand and combat disease.
Organisations
People |
ORCID iD |
| Nicholas C. Fletcher (Principal Investigator) |
Publications
Dabb SL
(2015)
mer and fac isomerism in tris chelate diimine metal complexes.
in Dalton transactions (Cambridge, England : 2003)
Filby MH
(2011)
Protein surface recognition using geometrically pure Ru(II) tris(bipyridine) derivatives.
in Chemical communications (Cambridge, England)
Hewitt SH
(2017)
Protein Surface Mimetics: Understanding How Ruthenium Tris(Bipyridines) Interact with Proteins.
in Chembiochem : a European journal of chemical biology
Phillips HI
(2012)
The use of electrospray mass spectrometry to determine speciation in a dynamic combinatorial library for anion recognition.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Wilson AJ
(2013)
Protein destabilisation by ruthenium(II) tris-bipyridine based protein-surface mimetics.
in Organic & biomolecular chemistry
| Description | The transition metal complexes used in this study can disrupt biological function, typically by using a small appended recognition unit complementary to a specific and identified enzyme binding site. Whilst the use of small molecules with well defined targets has been the initiation of much drug development, it is now recognized that many biological processes are governed by the more subtle interactions between proteins, and not just their metabolites. These occur through contact between relatively large ill defined surfaces. Given the relatively poor understanding of these interactions, the development of pharmaceuticals to inhibit specific metabolic pathways using this approach remains limited. The objective of this collaborative project with the University of Leeds has been to demonstrate that functionalized metal tris(chelate) complexes can (a) be used as specific and selective receptors for protein-surfaces (b) be used to perturb protein-protein interactions. Key to this was the illustration by the collaborating group that they could use simple negatively charged materials as selective sensors for solvent exposed surfaces and that the relative orientation of the protein binding groups appended to a metal core plays a critical role in determining the affinity towards the targeted protein. Through the course of this study, isolated transition metal complexes have been shown to disrupt specific protein-protein interactions, with cyctochrome c/ cytochrome c peroxidase, showing that it is indeed possible to identify specific and selective receptors for protein-surfaces. Given the observation that the arrangement of the appended functional groups appears to be very significant to the size of the observed interactions, a detailed review of the available synthetic methodologies to isolate molecules with different shapes (geometrical isomers; mer and fac) has been undertaken (publication now submitted for publication) and several new synthetic pathways have been attempted in the isolation of materials with a specific shape capable binding to protein surfaces (ongoing and unpublished work). From the outset of the study, it was recognized that the complexity of the necessary synthetic work to provide a suite of materials to optimize the recognition of protein surfaces was going to be prohibitive due to the labour required to complete such a task. To overcome this, we have also shown that a dynamic combinatorial library of labile model complexes can be used, directed by the addition of an external stimulus, and significantly we have validated that the process can be monitored by mass spectrometry. We have subsequently shown that proteins can act as templates to promote the formation of a models complex demonstrating proof of concept informing the study of the targeted synthesis. The work attempted, whilst both challenging and ambitious, has been a major success resulting in a number of collaborative publications, with work presented at three international conferences and several smaller UK meetings. |
| Exploitation Route | The outcomes of the research provided a number of new avenues of research including; 1. Expanding the number of protein - protein contacts that can be specifically inhibited which should be of interest in inhibiting a number of metabolic processes. 2. The identification of new synthetic routes to previously inaccessible materials with very specific and well controlled geometries has open up new avenues of on-going research. 3. The demonstration that a combinatorial library can be monitored in situ with mass spectrometry has provided a new protocol that is being exploited in the determination of appropriate sensors for environmentally important anions, and for the selective recognition of secondary structures in DNA. |
| Sectors | Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology |
| Description | These findings have been reported in the scientific literature and at academic conferences, with the intention of reaching a broader audience to generate interest and opportunities for knowledge transfer and commercialisation. The knowledge obtained has been used to inform on-going research projects within the research groups in Leeds and Belfast. But it is also drawing interest with regard to application of both the inhibition of protein-protein interactions and the development of the mass spectrometry protocols from interested researchers in areas beyond those directly related to this particular field of research, as demonstrated by the good citations for the papers pulished so far. Further publications resulting from the outcomes of this research are planned. |
| First Year Of Impact | 2012 |
| Sector | Chemicals,Pharmaceuticals and Medical Biotechnology |
| Impact Types | Societal |