Background: Many proteins are considered ‘undruggable’ because of their large, flat, and featureless target interfaces. Constrained peptides, which fill a gap between classical small molecules and large antibody therapeutics, have potential to inhibit these challenging protein targets with high specificity. However, effective design strategies to capture the therapeutic potential of peptides are still needed to enable development of new drugs leads and for their translation.
Aims and Methods: We employ approaches guided by structure. (i) The first approach involved analysis of target surface structure to identify cryptic sites and further optimisation to improve stability [1, 2]. (ii) The second approach was based on structure mimicry of an endogenous binding partner and grafting onto an ultrastable disulfide-rich peptide scaffold [3]. We investigated two difficult-to-inhibit targets, PCSK9 for lowering cholesterol and preventative cardiovascular care, and PD-L1 for modulation of immune checkpoint inhibitors and cancer treatment.
Results: To validate our structure-based approaches we heavily rely on solution NMR. Activity was validated using a series of in vitro (SPR, ITC, ELISA), cellular, and in vivo assays. We successfully generated potent lead peptides with affinities in the pico- to nanomolar range [1, 2, 3].
Significance: The success of the strategies in generating potent peptide inhibitors suggest they could be of broad interest, as many protein-protein interactions remain underexplored due to their challenging topological nature. Indeed, a bioinformatic analysis of the peptide:protein structures indicated our cyclisation approach could have broad utility. At present, there are >60 peptide drugs in market with peptide drugs being activity pursued by all major pharmaceutical companies.