Related Experiment Video
Updated: Apr 21, 2026
12:14
A Converging Strategy for the Generation of a Virtually Sequenced cDNA Library from Unreferenced Pacific Oysters
Published on: June 13, 2019
6.0K
A Synergistic Inhibitor Development Strategy Against Human UDP-Galactose-4-Epimerase
William M Browne1,2, Jonathan Pettinger3, Teresa Weckwerth1,2
1Chemical Glycobiology Laboratory, Francis Crick Institute, London, UK.
Angewandte Chemie (International Ed. in English)
|April 20, 2026
Summary
Researchers developed novel small-molecule inhibitors for UDP-galactose-4-epimerase (GalE), a key enzyme in O-GalNAc glycosylation. This breakthrough offers new therapeutic strategies for cancer by targeting GalE, a promising oncology target.
Area of Science:
- Biochemistry
- Chemical Biology
- Drug Discovery
Background:
- O-GalNAc glycosylation is a crucial posttranslational modification in mammals.
- Its dysregulation is linked to cancer metastasis and immune evasion, but mechanistic insights are limited by a lack of chemical tools.
- UDP-galactose-4-epimerase (GalE) is essential for O-GalNAc biosynthesis, making it a potential therapeutic target.
Purpose of the Study:
- To develop novel small-molecule inhibitors targeting the enzyme GalE.
- To establish an efficient workflow combining covalent and non-covalent fragment screening with structure-based design.
- To identify potent inhibitors for GalE, addressing the need for chemical tools in O-GalNAc glycosylation research.
Main Methods:
- Integrated covalent and high-throughput crystallographic non-covalent fragment screening.
- Structure-based drug design strategies.
- Identification of a ligandable pocket near a reactive tyrosine residue in GalE.
Main Results:
- Discovery of a potent sulfonyl fluoride covalent inhibitor targeting a non-cysteine residue.
- Development of a covalent alkyne probe.
- Identification of nanomolar non-covalent and covalent binders using structure-enabled fragment screening.
Conclusions:
- Demonstrated a synergistic approach for GalE inhibition using next-generation chemical matter.
- Highlighted the potential for targeting non-cysteine residues in chemical biology.
- Provided valuable tools for studying O-GalNAc glycosylation and developing new oncology therapeutics.
More Related Videos
Related Concept Videos
01:27Combined Effects of Drugs: Synergism
8.0K
Synergism is a useful mechanism where combining two or more drugs is more effective than each constituent used alone. Such combinations are also called supra-additive interactions. The drugs collectively enhance the final therapeutic effect by acting on different targets. Another advantage is that the low dose of each constituent drug is sufficient to achieve the desired effect. This helps reduce the duration of therapy and lower the adverse effects of these drugs.
Such synergistic combinations...
Such synergistic combinations...
8.0K
01:23Inhibitors of Gram-positive Cell Wall Synthesis
131
Bacterial cell walls are typically rigid structures composed mainly of peptidoglycan, a mesh-like polymer that provides mechanical strength and maintains cell shape. The synthesis of peptidoglycan is a crucial process in bacterial growth and serves as a primary target for many antibiotics.Mechanism of Action of Beta-Lactam AntibioticsBeta-lactam antibiotics, such as penicillin, inhibit peptidoglycan synthesis in actively growing cells. These antibiotics share a characteristic four-membered...
131
01:52Eukaryotic Transcription Inhibitors
11.7K
Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
11.7K
01:27Pharmacogenetics of Phase II Enzymes: N-acetyltransferase, Thiopurine S-methyltransferase, UDP-glucuronosyltransferase
85
Phase II biotransformation reactions are essential for detoxifying and eliminating xenobiotics, including many pharmaceutical compounds. These reactions typically involve conjugation, the covalent attachment of polar endogenous groups such as glucuronic acid, sulfate, methyl, or acetyl moieties to functional groups introduced during Phase I metabolism. The resulting conjugates are more water-soluble, enabling efficient renal or biliary excretion.The major classes of Phase II enzymes include...
85
01:26Biosynthesis of Polysaccharides
981
Polysaccharides such as glycogen and starch are synthesized from nucleoside diphosphate sugars, primarily uridine diphosphate glucose (UDPG) and adenosine diphosphate glucose (ADPG). These activated glucose donors act as key intermediates in carbohydrate metabolism and biosynthesis. UDPG primarily involves glycogen synthesis in animals and many bacteria, while ADPG plays a fundamental role in starch synthesis in plants and certain bacteria.UDPG is formed when glucose-1-phosphate reacts with...
981