Expediting glycosaminoglycan synthesis: expanding frontiers for carbohydrate chemical biology
Lead Research Organisation:
Keele University
Department Name: Faculty of Natural Sciences
Abstract
This UKRI Fellowship will support my development of a new scientific expertise at Keele University which interfaces chemistry and biology. The overarching goal of the research is to develop an efficient technology to provide biologically important carbohydrates. Specifically, a class of oligosaccharides (where multiple carbohydrate monomers are linked together to form a chain) called heparan sulfates. Heparan sulfates are very important regulators within biology, mediating pathological conditions including cancer, Alzheimer's disease, viral infections such as HIV and HSV and numerous bacterial infections. Therefore, there is a real need to interrogate and fundamentally understand the biological role that heparan sulfate plays in these processes. This will allow scientists to formulate a precise picture of heparan sulfate-mediated structure-activity relationships and initiate the development of new treatments for the pathophysiologies that they control.
Chemical synthesis of heparan sulfates is particularly challenging and has traditionally always been completed using solution-phase reactions. Whilst there have been significant achievements in this field, the time and resource required to enable such 'total' syntheses is vast and more efficient methods must be found. This challenge will be addressed by automating heparan sulfate production using a machine-based synthesis and then modifying the materials obtained with enzymes to install specific features that enable their biological function. Such a methodology would revolutionise how quickly we can access these materials, which is absolutely necessary to study and understand their ubiquitous regulatory biology.
In undertaking this research, I will adopt a multidisciplinary approach consisting of a fusion between traditional organic chemistry, the evolving field of synthesis automation, and the innovative field of chemoenzymatic modification. This combination will facilitate the development of a faster and greener approach to biologically relevant heparan sulfates and overcome the current challenges presented in the building of biologically important carbohydrates. This is a rapidly evolving worldwide field which is currently underrepresented in UK science. The important materials provided by the technology and knowledge developed during this Fellowship will be used to probe these mechanisms of disease and aid the design and development of new therapeutics against them.
Chemical synthesis of heparan sulfates is particularly challenging and has traditionally always been completed using solution-phase reactions. Whilst there have been significant achievements in this field, the time and resource required to enable such 'total' syntheses is vast and more efficient methods must be found. This challenge will be addressed by automating heparan sulfate production using a machine-based synthesis and then modifying the materials obtained with enzymes to install specific features that enable their biological function. Such a methodology would revolutionise how quickly we can access these materials, which is absolutely necessary to study and understand their ubiquitous regulatory biology.
In undertaking this research, I will adopt a multidisciplinary approach consisting of a fusion between traditional organic chemistry, the evolving field of synthesis automation, and the innovative field of chemoenzymatic modification. This combination will facilitate the development of a faster and greener approach to biologically relevant heparan sulfates and overcome the current challenges presented in the building of biologically important carbohydrates. This is a rapidly evolving worldwide field which is currently underrepresented in UK science. The important materials provided by the technology and knowledge developed during this Fellowship will be used to probe these mechanisms of disease and aid the design and development of new therapeutics against them.
Planned Impact
Personal Impact:
This Fellowship embodies the flexibility and opportunity needed to for me establish competence in new scientific methodologies (biochemistry and automation methods) which underpins my establishing a world-leading capability for the expedited provision of structurally defined carbohydrates; this will deliver a huge personal impact for my scientific career.
The impact of this research could also be measured upon new, budding scientists. The School of Chemical and Physical Sciences at Keele is nationally renowned for its inspirational teaching (TEF Gold award), exemplified by a commitment to include cutting edge, research driven scientific content in undergraduate teaching. In a continuation of this philosophy, the staff and student cohort at Keele will benefit from the Fellowship as the research results arising will be incorporated into lectures, and also shared with undergraduate research students completing final year MChem research projects in my group.
Societal Impact
There are just under a thousand cancer diagnoses every day in the UK. Scientific research that can provide materials to explore the pathophysiology of the disease and offer new insight into targets for treatment will be of profound benefit to society. This Fellowship will provide a streamlined methodology for accessing structurally defined carbohydrate materials, essential to study the chemical biology of an enzyme upregulated in tumour metastasis and attributed to a worsened clinical prognosis. In addition, the class of materials targeted in this Fellowship, the glycosaminoglycans, are hugely involved in regulating a number of other disease states that have a deleterious effect on society e.g. Alzheimer's disease and bacterial infection. New chemical tools to better understand these processes will also be assessable more quickly using this Fellowship technology. High quality research published from this Fellowship will therefore create significant public interest in the area because it has a direct impact on quality of people's lives and health. We will strive to engender public enthusiasm by using print and digital media and exhibitions to communicate the role chemistry and biological chemistry play in targeting new medicine development, just as it has continued to do over the last century. Highly publicised and cited work will serve to raise the UK global profile of the disciplines combined in this Fellowship, facilitating new international collaborations, but also encouraging new generations of UK organic chemists to consider more interdisciplinary research career paths.
Economic Impact
The research proposed in this application has great potential impact on the UK pharmaceutical and biomaterial companies working in the areas of chemotherapy treatment and biomaterial applications respectively. The need for faster and greener methods to access biologically relevant and non-native carbohydrate systems will bring forward the opportunity to engage with these exciting biomolecules.
This Fellowship embodies the flexibility and opportunity needed to for me establish competence in new scientific methodologies (biochemistry and automation methods) which underpins my establishing a world-leading capability for the expedited provision of structurally defined carbohydrates; this will deliver a huge personal impact for my scientific career.
The impact of this research could also be measured upon new, budding scientists. The School of Chemical and Physical Sciences at Keele is nationally renowned for its inspirational teaching (TEF Gold award), exemplified by a commitment to include cutting edge, research driven scientific content in undergraduate teaching. In a continuation of this philosophy, the staff and student cohort at Keele will benefit from the Fellowship as the research results arising will be incorporated into lectures, and also shared with undergraduate research students completing final year MChem research projects in my group.
Societal Impact
There are just under a thousand cancer diagnoses every day in the UK. Scientific research that can provide materials to explore the pathophysiology of the disease and offer new insight into targets for treatment will be of profound benefit to society. This Fellowship will provide a streamlined methodology for accessing structurally defined carbohydrate materials, essential to study the chemical biology of an enzyme upregulated in tumour metastasis and attributed to a worsened clinical prognosis. In addition, the class of materials targeted in this Fellowship, the glycosaminoglycans, are hugely involved in regulating a number of other disease states that have a deleterious effect on society e.g. Alzheimer's disease and bacterial infection. New chemical tools to better understand these processes will also be assessable more quickly using this Fellowship technology. High quality research published from this Fellowship will therefore create significant public interest in the area because it has a direct impact on quality of people's lives and health. We will strive to engender public enthusiasm by using print and digital media and exhibitions to communicate the role chemistry and biological chemistry play in targeting new medicine development, just as it has continued to do over the last century. Highly publicised and cited work will serve to raise the UK global profile of the disciplines combined in this Fellowship, facilitating new international collaborations, but also encouraging new generations of UK organic chemists to consider more interdisciplinary research career paths.
Economic Impact
The research proposed in this application has great potential impact on the UK pharmaceutical and biomaterial companies working in the areas of chemotherapy treatment and biomaterial applications respectively. The need for faster and greener methods to access biologically relevant and non-native carbohydrate systems will bring forward the opportunity to engage with these exciting biomolecules.
Organisations
- Keele University (Fellow, Lead Research Organisation)
- Max Planck Society (Collaboration)
- Iduron (Project Partner)
- University of York (Project Partner)
- University of North Carolina at Chapel Hill (Project Partner)
- Croda (United Kingdom) (Project Partner)
- University of Liverpool (Project Partner)
- University of St Andrews (Project Partner)
Publications
Ahmadipour S
(2022)
Synthesis of C6-modified mannose 1-phosphates and evaluation of derived sugar nucleotides against GDP-mannose dehydrogenase.
in Beilstein journal of organic chemistry
Ahmadipour S
(2021)
Prospects for anti-Candida therapy through targeting the cell wall: A mini-review.
in Cell surface (Amsterdam, Netherlands)
Benckendorff CMM
(2023)
Preparation of a 4'-Thiouridine Building-Block for Solid-Phase Oligonucleotide Synthesis.
in Current protocols
Benckendorff CMM
(2022)
Synthesis of fluorinated carbocyclic pyrimidine nucleoside analogues.
in Organic & biomolecular chemistry
Cosgrove S
(2023)
Realizing the Continuous Chemoenzymatic Synthesis of Anilines Using an Immobilized Nitroreductase
in ACS Sustainable Chemistry & Engineering
Cosgrove S
(2022)
Advances in biocatalytic and chemoenzymatic synthesis of nucleoside analogues
in Expert Opinion on Drug Discovery
Dolan J
(2023)
Fluorinated nucleosides, nucleotides and sugar nucleotides
in Future Medicinal Chemistry
Dolan JP
(2023)
Biocatalytic Approaches to Building Blocks for Enzymatic and Chemical Glycan Synthesis.
in JACS Au
Dolan JP
(2023)
Virtual screening, identification and in vitro validation of small molecule GDP-mannose dehydrogenase inhibitors.
in RSC chemical biology
Guinan M
(2022)
Design, chemical synthesis and antiviral evaluation of 2'-deoxy-2'-fluoro-2'-C-methyl-4'-thionucleosides
in Bioorganic & Medicinal Chemistry Letters
Guinan M
(2022)
Chemical synthesis of 4'-thio and 4'-sulfinyl pyrimidine nucleoside analogues.
in Organic & biomolecular chemistry
Keenan T
(2023)
Reverse thiophosphorylase activity of a glycoside phosphorylase in the synthesis of an unnatural Manß1,4GlcNAc library.
in Chemical science
Meneghetti MCZ
(2022)
Using NMR to Dissect the Chemical Space and O-Sulfation Effects within the O- and S-Glycoside Analogues of Heparan Sulfate.
in ACS omega
Motter J
(2024)
Purine nucleoside antibiotics: recent synthetic advances harnessing chemistry and biology.
in Natural product reports
Pongener I
(2023)
d-Glucuronate and d-Glucuronate Glycal Acceptors for the Scalable Synthesis of d-GlcN-a-1,4-d-GlcA Disaccharides and Modular Assembly of Heparan Sulfate.
in The Journal of organic chemistry
Pongener I
(2024)
Synthesis of a heparan sulfate tetrasaccharide using automated glycan assembly
in Organic & Biomolecular Chemistry
Pongener I
(2021)
Developments in the Chemical Synthesis of Heparin and Heparan Sulfate.
in Chemical record (New York, N.Y.)
Porter J
(2023)
Synthesis of 4-thio-d-glucopyranose and interconversion to 4-thio-d-glucofuranose.
in Carbohydrate research
Porter J
(2023)
Chemical synthesis of amphiphilic glycoconjugates: Access to amino, fluorinated and sulfhydryl oleyl glucosides
in Carbohydrate Research
Wahart AJC
(2022)
Oxidase enzymes as sustainable oxidation catalysts.
in Royal Society open science
Wahart AJC
(2024)
Harnessing a Biocatalyst to Bioremediate the Purification of Alkylglycosides.
in Chembiochem : a European journal of chemical biology
Description | Glyconeer |
Organisation | Max Planck Society |
Department | Max Planck Institute of Colloids and Interfaces |
Country | Germany |
Sector | Charity/Non Profit |
PI Contribution | Synthesis of building blocks for automated glycan assembly |
Collaborator Contribution | Use of glyconeer for automated glycan assembly |
Impact | / |
Start Year | 2022 |