A Platform for Chemical Probe Identification and Optimization Facilitating Interrogation of Biological Mechanisms
Lead Research Organisation:
University of Leeds
Department Name: Sch of Chemistry
Abstract
Enabling physical sciences methods are tremendously powerful in studying proteins - the workhorses of biology. Proteins perform a significant proportion of functions in cells to make life possible and interact with one another to regulate each other's functions. In this way, proteins control the majority of cellular processes that regulate life, therefore it is crucial that we continue to develop enabling physical sciences methods to underpin the study of protein function to deliver insights that improve food security alongside tools to diagnose and treat disease.
Synthetic chemical probes function by binding to protein targets and can do so either temporarily, or by linking permanently to their target. In either case, the field of "chemical proteomics" represents the approach by which interaction of a chemical probe with its protein target in cells is used to learn about the role of probe and/or protein in biology. Chemical probes can be small molecule drugs, other biologically active molecules, or tools to read-out the interactions of proteins, protein activity, or protein modifications that the cell uses to control protein function. To carry out chemical proteomics it is necessary to identify and quantify changes to proteins in the cell; this can be achieved using high-resolution mass-spectrometry. Mass-spectrometry is an analytical technique that measures the mass-to-charge ratio of ions; it requires only low sample quantities and can unambiguously identify and quantify individual proteins from cells and identify the cellular targets of synthetic chemical probes.
This strategic equipment initiative will install a new state-of-the-art mass-spectrometer at The University of Leeds making chemical proteomics possible for a large group of researchers developing chemical probes and investigating biological processes relevant to animals and plants, including cancer, dementia, cardiovascular disease and crop stress. This will generate considerable opportunities for intervening in biological processes (a) to understand healthy cells better (b) to develop new therapeutics (c) to improve food security.
Synthetic chemical probes function by binding to protein targets and can do so either temporarily, or by linking permanently to their target. In either case, the field of "chemical proteomics" represents the approach by which interaction of a chemical probe with its protein target in cells is used to learn about the role of probe and/or protein in biology. Chemical probes can be small molecule drugs, other biologically active molecules, or tools to read-out the interactions of proteins, protein activity, or protein modifications that the cell uses to control protein function. To carry out chemical proteomics it is necessary to identify and quantify changes to proteins in the cell; this can be achieved using high-resolution mass-spectrometry. Mass-spectrometry is an analytical technique that measures the mass-to-charge ratio of ions; it requires only low sample quantities and can unambiguously identify and quantify individual proteins from cells and identify the cellular targets of synthetic chemical probes.
This strategic equipment initiative will install a new state-of-the-art mass-spectrometer at The University of Leeds making chemical proteomics possible for a large group of researchers developing chemical probes and investigating biological processes relevant to animals and plants, including cancer, dementia, cardiovascular disease and crop stress. This will generate considerable opportunities for intervening in biological processes (a) to understand healthy cells better (b) to develop new therapeutics (c) to improve food security.
Description | Through this award an advanced nano-LC MS system (Bruker TIMS-TOF Pro) system was procured and installed and commissioned on site at the University of Leeds. This instrument is exceptionally sensitive and can perform the type of experiments used in chemical proteomics rapidly and with unparalleled sensitivity. A wide group of users have then used this instrumentation to determine how small chemicals made within several research groups bind to a number of protein targets and cause modifications. This includes the development of new chemical methods to enable chemical proteomic studies. Targets include proteins involved in cancer signalling pathways, tropical diseases and those involved in bacterial infections. These insights are helping us to reimagine how chemistry can be harnessed to understand biology, and then to understand the molecular basis of biomolecular interactions and develop new ways to modulate them. Alongside the technique development users have been trained in the analysis of proteomic software which is particularly data dense and requires specialist methods to analyse it. Some special tools for the analysis of chemical modifications including machine learning algorithms have been developed within the research team. |
Exploitation Route | This was underpinning strategic infrastructure funding which is now being harnessed in a wide range of interdisciplinary projects focussing on the development and applications of new chemical methods. This includes on goign and new collaborations with external national and international research organisations in both academia and industry. |
Sectors | Healthcare Manufacturing including Industrial Biotechology Pharmaceuticals and Medical Biotechnology |
Description | Autonomous Phenotype-Directed Molecular Discovery |
Amount | £1,184,398 (GBP) |
Funding ID | EP/W002914/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2022 |
End | 08/2025 |
Description | BubblEs for TArgeting and TReatment of biOfilm InfectioNs (BETATRON) |
Amount | £979,771 (GBP) |
Funding ID | EP/W033151/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 06/2022 |
End | 06/2025 |
Description | AZ |
Organisation | AstraZeneca |
Country | United Kingdom |
Sector | Private |
PI Contribution | Preparation and reactivity profiling of caged protein inhibitors |
Collaborator Contribution | synthetic advice and biological insights |
Impact | none yet |
Start Year | 2023 |
Description | GSK |
Organisation | GlaxoSmithKline (GSK) |
Department | Research and Development GSK |
Country | United Kingdom |
Sector | Private |
PI Contribution | chemistry to enable discovery of covalent ligands |
Collaborator Contribution | biological expertise |
Impact | none yet |
Start Year | 2023 |
Description | MaxPlanck |
Organisation | Max Planck Society |
Department | Max Planck Institute for Molecular Physiology |
Country | Germany |
Sector | Academic/University |
PI Contribution | chemistry to drive bioactive molecular discovery; chemical proteomics to enable determination of mode of action of discovered compounds |
Collaborator Contribution | phenotypic screening (cell painting assay) |
Impact | none yet |
Start Year | 2022 |
Description | UEA |
Organisation | University of East Anglia |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | performing Chemical proteomics analyses |
Collaborator Contribution | Preparation of Samples |
Impact | None at present |
Start Year | 2023 |
Description | • Schools Lecture, Notre Dame Catholic 6th Form College, Leeds (6th May 2022): "Research at the Interface Between Physical And Life Sciences" |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Schools Lecture, Notre Dame Catholic 6th Form College, Leeds (6th May 2022): "Research at the Interface Between Physical And Life Sciences" |
Year(s) Of Engagement Activity | 2022 |