Friday, 4 July 2025 11:00am – 12:00pm

This seminar will be delivered in Chemistry Lecture Theatre 4

Speaker: Dr Yun Shi

Host: Dr Constance Bailey

Title: Ligand Discovery for NAD+ Glycohydrolases

Abstract
Nicotinamide adenine dinucleotide (NAD+) is a ubiquitous biomolecule essential for cellular life. Beyond its role as a redox cofactor in energy metabolism, NAD+ serves as a substrate for NAD+-dependent signalling pathways. We have discovered the NAD+-glycohydrolysing activities of proteins with the Toll/interleukin-1/resistance (TIR) domain, including SARM1, a promising target against axon degeneration. Our work identified a base-exchange mechanism that enables in situ generation of potent SARM1 inhibitors from small-molecule fragments. Additionally, we uncovered novel NAD+ catabolites produced by other TIR-domain proteins through similar mechanisms, revealing the molecular basis of their signalling function in bacterial antiphage defence systems. We propose a fragment-based approach to develop additional in situ-generated base-exchange inhibitors targeting different NAD+ glycohydrolases.

Bio
Dr. Yun Shi is an ARC DECRA Fellow and an NHMRC Investigator (Emerging Leadership) with multiple high-impact publications in journals such as Science and Molecular Cell. He combines computational, biophysical, and biochemical approaches to investigate protein-ligand interactions. Dr. Shi joined Griffith University after obtaining a PhD in Chemistry from Simon Fraser University (2015). With a Griffith University Postdoctoral Fellowship (2016), he established a fragment-based drug discovery platform using nuclear magnetic resonance (NMR) spectroscopy as the primary technique. Dr. Shi’s current research focuses on the molecular function and inhibition of enzymes involved in nicotinamide adenine dinucleotide (NAD+) metabolism. These include NAD+ glycohydrolases and NAD+ synthases that are promising therapeutic targets against neurodegeneration and infectious diseases.