Periodic Reporting for period 2 - CPTarget (Cyclic Peptide Platform as an Approach to Target Validation)
Berichtszeitraum: 2023-04-01 bis 2024-09-30
The current ‘genomics’ era is an exciting time for drug target discovery with considerable opportunities for therapeutic intervention. Whilst classical small molecules remain the reagents of choice as chemical probes for target validation, not all targets are tractable with small molecules. There is thus an urgent need to develop methods for more efficient target validation, not only of individual proteins but also of protein-protein and other complexes. Natural product like cyclic peptides have enormous potential as a chemical platform for target validation. Recent technological advances have enabled the efficient production and screening of large libraries containing non-proteinogenic residues. De novo cyclic peptides with high affinity and selectivity for target proteins can be readily generated, even for protein-protein interaction targets perceived as challenging. Development of this technology and their innovative applications as outlined in our proposal will provide a step-change in methodology, and transform the current approach for studying the biological function of the target / pathways, enabling new ways to investigate potential targets. We aim to develop innovative chemical and molecular techniques to explore the applications of natural product-like cyclic peptides in target validation for very challenging targets. Ultimately the work aims to enable the development of new therapeutic agents targeting multiple diseases.
We have been developing an efficient and rapid platform for the identification and development of selective and potent cyclic peptides against targets of biomedical and therapeutic interest. We have applied this to a number of different protein targets and demonstrated proof of concept. This includes examples of potential therapeutic targets that are considered challenging by small molecules, including PHD-finger domains involved in epigenetic regulation, to therapeutically validated targets where efficient and rapid ligand discovery are needed. We have combined next-generation sequencing data to guide our hit selection to efficiently identify highly potent functional ligands against targets. Excitingly, we have also demonstrated that these cyclic peptides can be used to probe the target function or developed as chemical tools such as affinity and targeting probes.
We will continue to refine peptide discovery work further, and to explore the potential opportunities for different applications of the cyclic peptides in chemical biology and target discovery / validation.