Bisubstrate Ether-Linked Uridine-Peptide Conjugates as O-GlcNAc Transferase Inhibitors
Vivek Makwana1,2,3, Philip Ryan1,2,3, Alpeshkumar K Malde4,5
1Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD 4222, Australia.
Chemmedchem
|September 29, 2020
Summary
New O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) inhibitors were developed using a bisubstrate design. These compounds offer valuable tools for studying OGT
Area of Science:
- Biochemistry
- Chemical Biology
- Molecular Biology
Background:
- O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) regulates protein O-GlcNAcylation, a post-translational modification implicated in diabetes and cancer.
- Aberrant O-GlcNAcylation impacts cellular signaling pathways.
- Selective OGT inhibitors are crucial for dissecting OGT's diverse cellular roles.
Purpose of the Study:
- To design and synthesize novel OGT inhibitors.
- To evaluate the inhibitory potential and binding characteristics of these new compounds.
- To understand the structure-activity relationships for bisubstrate analogue inhibitors.
Main Methods:
- Synthesis of linear bisubstrate ether-linked uridine-peptide conjugates.
- In vitro enzymatic assays to determine inhibitor potency (micromolar affinity).
- Molecular dynamics simulations to elucidate binding modes and rationalize structure-activity relationships.
Main Results:
- Developed novel OGT inhibitors with micromolar affinity.
- Demonstrated the significance of donor substrate, linker, and acceptor peptide in inhibitor design.
- Identified the impact of acceptor peptide amino acid truncation on OGT inhibition through simulations.
Conclusions:
- Linear bisubstrate ether-linked uridine-peptide conjugates represent a promising class of OGT inhibitors.
- Rational design principles were established for developing potent bisubstrate analogue inhibitors.
- Molecular dynamics simulations provide insights into inhibitor binding and guide future optimization.
