Small molecules (MW < 500 Da) are a well-established class of drugs commonly used to treat a variety of diseases by targeting deep and well-defined pockets of proteins, enzymes, receptors, ion-channels etc. However, more than 80% of the signaling pathways that regulate important physio-pathological mechanisms are characterized by molecular interactions at shallow and undefined pockets, such as those found at the interface of many protein-protein interactions (PPIs). Molecules able to interact with these shallow pockets may unlock a number of diseases that can be investigated and treated. Peptides are the perfect molecules to modulate such targets, considering that they mimic the endogenous portion of the interacting proteins. In addition, peptides show low toxicity, can be easily synthesized, and are more tissue permeable than other biologics. Several peptides have been successfully developed and used to target intracellular and extracellular PPIs over the past couple of decades, although only a small percentage of them appear to have been stable in the living organism. Peptides, in fact, are characterized by poor chemical and enzymatic stability resulting in a short half-life and poor membrane permeability.
Among the different strategies used to improve the pharmacokinetic properties of peptides, cyclization is probably the most widely used.
In the Spring group, our research has focused on the development of novel two-component peptide stapling methodologies and their application to biologically relevant targets (including MDM2/p53, CK2, BH3-proteins, TNKS). A few representative examples of our recent research on MDM2/p53 PPI are shown in the Figure below.
Examples of application of our 2C-PS methodologies. We use our methodologies to generate biocompatible stapling reactions, to synthesise peptides with functionalized staples including CPP tags, fluorescent motifs, functionalities for pull-down assays, motifs to achieve targeted covalent inhibition (figure created with BioRender.com).
Currently, we continue to explore novel ways of overcoming the limitations of peptides with the development of novel stapling methodologies. Simultaneously, we are exploring next-generation peptides - e.g. peptide-drug conjugates, controlled-release devices, PPI inhibitors for new targets - to provide chemical tools that could help the scientific community to develop life-changing medicines.
Our research utilises state-of-the-art synthetic methodologies to make libraries of stapled peptides. Biophysical and biological assays are crucial to the success of our peptide projects and for that we have established strong collaborations with the Hyvönen group (Department of Biochemistry, University of Cambridge), the Itzhaki group (Department of Pharmacology, University of Cambridge) and AstraZeneca.