Oral Presentation Royal Australian Chemical Institute National Congress 2026

Engineering Covalent Peptides to Unlock Novel Therapeutic Targets in Alzheimer’s Disease (138169)

Reuben Blades 1 , Jack Vozzo 1 , Kanishka Pushpitha 1 , Nicholas Solomon 1 , Daryl Ariawan 1 , Gene Hart-Smith 1 , Lars Ittner 1 , Ole Tietz 1
  1. Macquarie University, Macquarie Park, NSW, Australia

Alzheimer's disease (AD) is a progressive neurodegenerative condition afflicting millions of patients worldwide. The disease is characterized by accumulation of amyloid-β (Aβ) peptides and hyperphosphorylated tau proteins in the brain resulting in neuronal loss and cognitive decline. The tau protein is an intrinsically disordered protein (IDP) that has diverse and crucial neuronal functions, including post-synaptic signalling in the mature brain. Tau is a promising target for the development of novel therapeutics to treat Alzheimer’s Disease; however, it’s intrinsically disordered nature makes the identification of interaction partners and the development of small molecule therapeutics a major challenge.

To address this problem, we have developed an integrated drug discovery platform that uses tau peptides engineered for protein-peptide interface dependent covalent crosslinking. We demonstrate that this platform can aid drug discovery through three key steps:

  • Identification of novel therapeutic targets - covalent peptides are used to identify novel interacting proteins responsible for tau signalling and trafficking in cell lysates and animal tissues, including transgenic mouse models of AD
  • Structural characterization of protein-peptide complexes – tryptic digest of complexes followed by mass spectrometry analysis identified interacting residue pairs to pin-point hotspots on the protein interface for in silico discovery of small molecule therapeutics.
  • Identification and assay of novel therapeutics – following in silico drug discovery, covalent peptides are used to assay compound libraries and triage compounds by protein-protein inhibition efficacy.

This Drug Discovery platform resolves a key hurdle in the development of new drugs with novel mechanisms of action for the treatment of Alzheimer’s Disease, with potential further application in drug discovery for other neurodegenerative diseases and non-neuroscience fields.