Antibody mimetic peptides
Peptide macrocycles are a class of compounds that can bind with high affinity and selectivity to peptides, thereby comprising attractive therapeutic candidates. A recently developed technique based on the phage display method has allowed the generation of potent bicyclic peptide antagonists. However, it proved difficult to obtain high-affinity molecules against proteins with flat surfaces and no clefts or cavities. To address this issue, scientists on the EU-funded CYPEPUTICS (Tricyclic peptides for the development of therapeutics) project proposed to develop 3D rigid tricyclic peptide scaffolds that, similarly to antibodies, can bind to flat surfaces. In this context, they generated a cyclic hexa-peptide consisting of six amino acids with two anchored peptide loops, which resembled the complementarity determining regions of antibodies. As a first step, researchers optimised the synthesis of the cyclic hexa-peptides and of the model linear peptides that consisted of a certain motif with three cysteine amino acids to allow loop formation. The procedure then had to be further adapted for peptide expression on phage. The consortium followed a phage display-based approach to screen large combinatorial libraries of antibody mimetics. In brief, they expressed the random peptides and displayed them on phage prior to chemically linking them to the cyclic hexa-peptide. Subsequent affinity selection led to the identification of tricyclic peptides that could bind to a variety of biological targets such as urokinase plasminogen activator and vascular endothelial growth factor. Taken together, the activities of the CYPEPUTICS project provide a basis for bringing peptide antibody mimetics a step closer to therapeutic applications. Their small size, which is expected to improve localisation in the desired tissue, their ease and cost-effectiveness of production make antibody mimetics a more attractive candidate compared to antibodies.
Keywords
Antibody mimetic, peptides, phage display, tricyclic peptides, cyclic hexa-peptide, amino acids
