ChemGlycoSEPSIS - Chemical glycobiology for the study and exploitation of pseudaminic acid sugars in infectious diseases
Lead Research Organisation:
University of York
Department Name: Chemistry
Abstract
Sugars, or glycans as they are commonly known, are the most abundant biomolecule on earth and play essential roles in a myriad of
biological processes including energy storage, cell-cell recognition and the immunological response. The ubiquitous 'sialic acid' sugar
Neu5Ac is present on the surface of all human cells and is therefore well studied, but its 'evil twin' pseudaminic acid (Pse), which is
present in a range of bacteria, is poorly understood in comparison. Pse is highly prevalent on the surface of a number of bacterial
species including multidrug resistant ESKAPE pathogens P. aeruginosa and A. baumannii, and gastric pathogens C. jejuni and H.
pylori, and it is now increasingly clear that Pse presentation and editing is important for virulence. But despite its discovery over thirty
years ago our understanding of exactly how and why bacteria choose to decorate their surfaces with this sugar is in its infancy. This is
primarily because Pse is fiendishly complex and therefore challenging to synthesise and study. In ChemGlycoSEPSIS will we therefore
develop an unprecedented chemical glycobiology toolkit which will deliver Pse based enzyme substrates, probes and inhibitors to
enable dissection of the bacterial 'Pseome'- and in the process establish the field of Pse chemical enzymology. Across three
transdisciplinary work-packages, we will unpick how Pse glycans are processed by bacteria and how they interact with host cells.
Specifically we will focus on WPA: the dissection, discovery and inhibition of 'Pse Writers' ; WPB: the dissection,
discovery and inhibition of 'Pse Erasers'; and WPC: the exploration and inhibition of binding to 'Pse
Readers' . To date none of these biological processes have been unequivocally characterised so we will not only deliver
transformational molecular level insight into glycan processing but also novel cellular probes and therapeutic leads for treating
infections.
biological processes including energy storage, cell-cell recognition and the immunological response. The ubiquitous 'sialic acid' sugar
Neu5Ac is present on the surface of all human cells and is therefore well studied, but its 'evil twin' pseudaminic acid (Pse), which is
present in a range of bacteria, is poorly understood in comparison. Pse is highly prevalent on the surface of a number of bacterial
species including multidrug resistant ESKAPE pathogens P. aeruginosa and A. baumannii, and gastric pathogens C. jejuni and H.
pylori, and it is now increasingly clear that Pse presentation and editing is important for virulence. But despite its discovery over thirty
years ago our understanding of exactly how and why bacteria choose to decorate their surfaces with this sugar is in its infancy. This is
primarily because Pse is fiendishly complex and therefore challenging to synthesise and study. In ChemGlycoSEPSIS will we therefore
develop an unprecedented chemical glycobiology toolkit which will deliver Pse based enzyme substrates, probes and inhibitors to
enable dissection of the bacterial 'Pseome'- and in the process establish the field of Pse chemical enzymology. Across three
transdisciplinary work-packages, we will unpick how Pse glycans are processed by bacteria and how they interact with host cells.
Specifically we will focus on WPA: the dissection, discovery and inhibition of 'Pse Writers' ; WPB: the dissection,
discovery and inhibition of 'Pse Erasers'; and WPC: the exploration and inhibition of binding to 'Pse
Readers' . To date none of these biological processes have been unequivocally characterised so we will not only deliver
transformational molecular level insight into glycan processing but also novel cellular probes and therapeutic leads for treating
infections.
Organisations
People |
ORCID iD |
| Martin Fascione (Principal Investigator) |
Publications
Keenan T
(2024)
Co-factor prosthesis facilitates biosynthesis of azido-pseudaminic acid probes for use as glycosyltransferase reporters.
in Chemical communications (Cambridge, England)
Keenan T
(2023)
Reverse thiophosphorylase activity of a glycoside phosphorylase in the synthesis of an unnatural Manß1,4GlcNAc library.
in Chemical science
Walklett AJ
(2024)
The Retaining Pse5Ac7Ac Pseudaminyltransferase KpsS1 Defines a Previously Unreported glycosyltransferase family (GT118).
in Angewandte Chemie (International ed. in English)
Yates NDJ
(2023)
Site-Selective Aryl Diazonium Installation onto Protein Surfaces at Neutral pH using a Maleimide-Functionalized Triazabutadiene.
in Chembiochem : a European journal of chemical biology
Yates NDJ
(2024)
Crossing the Solubility Rubicon: 15-Crown-5 Facilitates the Preparation of Water-Soluble Sulfo-NHS Esters in Organic Solvents.
in Bioconjugate chemistry
Yates NDJ
(2023)
Preparation and Application of an Inexpensive a-Formylglycine Building Block Compatible with Fmoc Solid-Phase Peptide Synthesis.
in Organic letters