Peptide and peptide-inspired checkpoint inhibitors: Protein fragments to cancer immunotherapy

Immune system regained the attention of oncologists and has entered the mainstream for cancer therapy since the discovery of checkpoint antibodies targeting CTLA4 and PD-1 pathways. Efficacy in only a subset of patient population observed with the current checkpoint inhibitors is considered as one of the major limitations of this approach. A number of strategies including combination with newer checkpoint antibodies and tumor-targeted agents as well as blocking checkpoint proteins with alternate approaches are being evaluated to overcome the restricted efficacy. This review provides an overview of checkpoint protein superfamily and the nature of the interacting interface of checkpoint receptors and ligands, and explores the potential advantages of peptide or a peptide-based checkpoint inhibitor approach that mimic the native interaction interface. Additionally, the review covers the rationale and strategies for peptides/peptidomimetics discovered against various checkpoint proteins, and transformation of a few such peptides to peptide-inspired orally bioavailable agents for cancer immunotherapy.