Building a Chemical Toolbox

Title: Building a Chemical Toolbox

Speaker:  A/Prof Santosh Rudrawar, Institute for Biomedicine and Glycomics, Griffith University

Abstract: This presentation outlines a unified chemical biology approach to developing a versatile “chemical toolbox” for addressing challenges in neurodegeneration, cancer and antibacterial drug discovery.

Part 1: Targeting O-GlcNAcylation in Neurodegeneration and Cancer

Neurodegenerative diseases such as Alzheimer’s and Parkinson’s are characterised by the aggregation of misfolded proteins, including tau, amyloid-β, and α-synuclein. The dynamic post-translational modification O-GlcNAcylation, regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), plays a critical role in maintaining protein homeostasis. Dysregulation of this pathway contributes to neurodegenerative diseases and cancer, making it an attractive therapeutic target. We describe the design of bisubstrate OGT inhibitors that simultaneously mimic donor (UDP-GlcNAc) and peptide acceptor substrates. Using solid-phase peptide synthesis and nucleoside-based strategies, a library of uridine-derived conjugates incorporating varying linkers was developed, providing mechanistic insights into enzyme inhibition. To probe disease relevance, site-specific glycopeptides were synthesised to examine α-synuclein aggregation. O-GlcNAc modification within the NAC domain significantly reduces fibril formation, with biophysical assays demonstrating up to 50% inhibition. Complementary small molecules, including chalcones and pyrazoline derivatives, further expand the toolkit for modulating aggregation.

Part 2: Simplified Nucleoside Antibiotics

The second theme focuses on muraymycin-inspired nucleoside antibiotics. Guided by structure–activity relationships, simplified analogues incorporating a uridine core, aminoribose unit, and lipophilic side chain were synthesised using a serine-templated approach. Preliminary biological evaluation reveals promising antibacterial activity, highlighting their potential as leads for further optimisation. Together, these studies demonstrate how integrated chemical tools can advance mechanistic understanding and therapeutic development across neurodegenerative, cancer and infectious diseases. 

Biography: Santosh Rudrawar completed his PhD at the National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, India, in 2008 under the supervision of Prof Asit K Chakraborti FRSC. Following this, he joined Prof Mark von Itzstein AO’s group at the Institute for Glycomics, Griffith University, Australia, as a postdoctoral research associate. In 2013, he moved to the University of Sydney’s School of Chemistry, working with Prof Richard Payne as a postdoctoral fellow. In 2014, he was awarded the Australian Research Council Discovery Early Career Research Award, marking the beginning of his independent research and teaching career. He returned to Griffith University in 2016 as a Lecturer in the School of Pharmacy and Medical Sciences. He is currently a Research Leader at the Institute for Biomedicine and Glycomics and Associate Professor in the School of Pharmacy and Medical Sciences. His research spans medicinal and organic biomolecular chemistry, with a focus on neurodegeneration, cancer, and antibiotic resistance. His current interests include developing reagents and probes to study carbohydrate-processing enzymes and carbohydrate-binding proteins.