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 employed two novel approaches for design of potent lead peptides. (i) The first involved use of recombinant libraries to engineer bioactive cyclisation linkers to achieve a two-in-one effect of stabilisation and increased activity [1]. (ii) The second was a structural mimicry approach using in silico designed ultrastable disulfide-rich scaffolds [2]. 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: We successfully generated potent lead peptides with potent affinities in the pico- to nanomolar range [1, 2]. Activity was comprehensively validated using a series of structural (NMR, X-Ray, MD), in vitro (SPR, ITC, ELISA, FP), cellular, and in vivo assays [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 all peptide:protein structures indicated our cyclisation approach could have broad utility [1]. At present, there are >60 peptide drugs in market with peptide drugs being activity pursued by all major pharmaceutical companies.