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Scholar Profiles

Yu Heng Lau

Yu Heng Lau

Country of origin: Australia

Subject: Chemistry

Matriculation year: 2010

During my PhD, I explored new chemical strategies to block the interactions between pairs of proteins that drive cancer progression, as a potential avenue for therapeutic development.  Our strategy was to design and synthesise molecules that could mimic the structure of the binding interface between two proteins of interest. Starting with short linear peptide fragments copied from one of the proteins in the pair, we developed methods to cyclise these linear precursors using synthetic bridging linkers called ‘staples’. This process resulted in modified cyclic peptides that had the requisite structural rigidity to mimic and bind with high specificity and affinity at the protein-protein interface.  

Having developed the chemical methodology for peptide cyclisation, we synthesised a range of cyclic peptides to inhibit various cancer-associated protein targets, including p53/MDM2, tankyrase, and the Ctf4 genome stability hub, and demonstrated inhibitory effects in biophysical assays and cell-based studies. While conducting these biological experiments, we were surprised to find that our design choices in the ‘staple’ component of our molecules had a profound effect on the inhibitory activity. Previous studies had considered the ‘staple’ linkage primarily as a structural scaffold, whereas we found that the chemical features of this linkage were also crucial. Inspired by this work amongst others, many studies have now explored chemical variations on this linkage motif, towards the development of therapeutic candidates with superior properties.

Therapeutic development is rarely a rapid process, and as such, the full long-term impact of my PhD research remains to be seen! The field of peptide therapeutics is still going strong, and we are optimistic that with continued research, this class of molecules will provide us with inhibitors of protein-protein interactions with sufficient efficacy to lead to new approved medicines.