Traditional drug discovery efforts are often plagued by the linear nature of most synthetic strategies, the lack of structural diversity obtained from compound library synthesis and from the difficulty in rapidly screening a compound library against a particular drug target. Aptamers are small single-stranded nucleic acid molecules that fold into well-defined three-dimensional structures. These interact with proteins and other nucleic acids with high affinity and specificity, but are normally restricted to nucleic acids. This project will develop novel aptamer libraries using peptide nucleic acid (PNA) molecules as binding ligands instead of DNA or RNA. PNAs combine the hybridisation properties of DNA with the modularity and molecular diversity of peptides and will therefore lead to structurally unique scaffolds for drug discovery applications. The project will build upon cutting-edge templated peptide ligation technologies developed in a recently established, highly fruitful collaboration between the Payne laboratory at the University of Sydney and the Winssinger at the University of Geneva. The collaborative project will enable the development of libraries of peptide-PNA hybrid aptamers that can be used to select and enrich PNA topological folds that can inhibit enzyme activities and protein-protein interactions for drug discovery campaigns. As a starting point, the project will develop PNA-based aptamers that possess anti-inflammatory activity through antagonism of two receptors (CCR2 and CCR5) that are targets for anti-inflammatory drugs. The project will lead to numerous outcomes including the elucidation of new therapeutic leads, publication of high impact papers, filed patents and interdisciplinary training of PhD students.
Prof Nicolas Winssinger, Chemistry, Faculty of Science
Prof Richard Payne, Chemistry, Faculty of Science