Enabling Phosphorus and Peptide based Chemical Biology using Ionic Liquids

Lead Research Organisation: Queen's University of Belfast
Department Name: Sch of Chemistry and Chemical Eng

Abstract

The objective of this multidisciplinary program is to develop unprecedented chemistry in ionic liquids (ILs) of immediate relevance to medical research programs currently pursued at QUB, and as such have a major impact on both the scientific and the clinical communities. Overall, these multidisciplinary projects will bring together phosphorus and protein chemistry, enabled by the use of ILs, for the development of novel chemical biology technologies, and diagnostic/therapeutic approaches. While the scientific community has made major progress in the field of phosphorus and protein chemistry, this has only been translated into progress for the end users such as biologists and clinicians via the intermediacy of the industrial community which makes available some of the chemicals that the biologists are in great need of and cannot access otherwise. While the industry provides a broad range of chemicals that enables biology and medical sciences, much research remains unchartered due to a lack of chemical availability. Often this limitation comes from a lack of chemical know-how or is simply due to the chemistry itself which also remains unchartered. This work aims at addressing this limitation in the field of phosphorus and peptide chemistry. Phosphorous agents have a major role to play in biology and are often needed to investigate biological events such as cell proliferation or cellular signaling. While many are commercially available, a lot are extremely expensive due to the difficulties encountered in their preparations. Similarly, while much could be gained by accessing similar compounds with very specific modifications, the current chemistry does not provide sufficient scope to allow access to these much needed biochemicals. We propose to use ionic liquids to manipulate phosphorous reagents so that the preparation of biologically relevant chemicals become more straight-forward with a lesser overall impact on the environment while minimising the number of steps required for their syntheses. In a similar manner protein chemistry and bioconjugation has greatly facilitated chemical biology and has enabled the development of very powerful therapeutics. To date, limited focus has been addressed to harnessing the chemical processes that encompass bioconjugation in order to try to modulate either the number of peptidic sites being modified on a given protein or the nature of the sites being modified. This is particularly relevant with the ever-increasing demand for the production of GMP material for therapeutic applications. Once again we propose to use ionic liquids to manipulate specific residues of small proteins for conjugation. Using ILs instead of the standard bioconjugation conditions so far developed will provide means to combine the chemical reactivity of many hydrophobic, water unstable reagents to that of the water-loving peptide side chains to access more readily a broader range of peptide linkers and peptide/protein modifiers.

Planned Impact

The communication of data generated from each activites undertaken in this project will be pursued subsequent to IP and issues of confidentiality being addressed and agreed by the PI/co-PIs while assisted by the Knowledge Exploitation Unit at Queen's University. Exploitation of data will be managed by the group, with Migaud as PI. Once IP related issues have been addressed, reports of activities (partially, individually or in association) will be disseminated at appropriate research conference(s) and in peer-reviewed publications where appropriate. However, the timeframe for these communications will be dictated by the novelty of the findings. Additionally, the individual groups have received support from numerous companies (Pharmas, Biotechs, etc...) in the past and it is anticipated that the newly generated results will further strengthen their collaborations through dessimination winth the industrial settings. The publication outputs are likely to exemplify the breadth of the science covered and it is anticipated that as a group results relating to this work will be published in a broad range of international journals in the fields of physical chemistry, microbiology, respiratory and cancer medicine which include Journal of Physical Chemistry, Green Chemistry and Chemical Communications, the Journal of Oncology, the Journal of Biological Chemistry and the Journal of Medicinal Chemistry as well as Nature and Science. In addition to these publications with the specific scientific communities, communication of our research will also be undertaken through a number of other mechanisms. For example, Migaud and Hardacre provide regular scientific reports to QUILL (see application for full details) and Prof Taggart is actively involved in the promotion of biotechnology in Northern Ireland through participation in InvestNI events such as technology showcases and international trade missions.
 
Description We demonstrated that the use of ionic liquids enabled nucleoside and dinucleoside synthesis. This has led to the publication of new chemistry
Exploitation Route The chemistry is now being considered for the production of commercial entities
Sectors Chemicals,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description new means to formulate polar molecules for delivery to sputum are now being developed for non-CF related conditions.
First Year Of Impact 2015
Sector Chemicals,Pharmaceuticals and Medical Biotechnology
 
Description "Merck KGaA,"
Amount £36,435 (GBP)
Funding ID EPSRC Knowledge Transfer Secondment Scheme 
Organisation Merck 
Sector Private
Country Germany
Start 01/2012 
End 12/2012
 
Description Pipe-line for rapid screening and rational improvement of nanoparticles for cancer imaging and
Amount £48,943 (GBP)
Funding ID ST/K001957/1 
Organisation Science and Technologies Facilities Council (STFC) 
Sector Public
Country United Kingdom
Start 10/2012 
End 08/2013
 
Description collaboration with Innovative DNA Technology 
Organisation Integrated DNA Technologies
Country United States 
Sector Private 
PI Contribution Work on ionic liquids stabilised phosphoramidite
Collaborator Contribution New reagents on which to apply ionic liquids technology
Impact NDA in place. Only chemistry
Start Year 2014