Beyond peptides: Unveiling the design strategies, structure activity correlations and protein-ligand interactions of...

The landscape of cancer treatment has been transformed by the emergence of immunotherapy, especially through the use of antibodies that target the PD-1/PD-L1 pathway. Recently, there has been a notable increase in interest surrounding immune checkpoint inhibitors for cancer therapy. While antibody-based approaches have drawbacks like high costs and prolonged activity, the approval of monoclonal antibodies such as pembrolizumab and nivolumab has paved the way for a range of alternative therapies, including peptides, peptidomimetics, and small-molecule inhibitors. These smaller molecules, which target the PD-1/PD-L1 interaction, are seen as potential substitutes or supplements to monoclonal antibodies. Our focus in this article is primarily on exploring small molecules designed for PD-1/PD-L1 checkpoint pathway modulation in cancer immunotherapy, along with highlighting current advances in their structural and preclinical/clinical development. The pursuit of therapeutics based on small-molecule inhibitors of the PD-1/PD-L1 axis offers a promising yet intricate avenue for advancing cancer treatment.