Research and development strategies for peptide drugs targeting protein-protein interactions
Protein-Protein Interaction (PPI) is involved in the regulation of many important cellular processes in organisms, such as cell proliferation, division, apoptosis, necrosis, and protein transcription and translation. There are about 130,000 PPIs in the human body, many of which are closely related to the occurrence and development of major diseases such as cardiovascular disease and cancer. Opening up PPI-type targets and developing their agonists or inhibitors has always been a frontier direction in the field of international innovative drug research and development.
At present, the marketed PPI drugs mainly include cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors (such as palbociclib, ribociclib and abemaciclib), checkpoint inhibitor PD-1/PD-L1 inhibitors (such as nivolumab and atezolizumab) and trastuzumab targeting the HER2 protein, these drug molecules are mainly divided into antibody and chemical small molecule drugs. Antibody molecules are difficult to reach intracellular targets due to their low cellular permeability, and the scope of drugs that can be developed is limited. In contrast, small-molecule drugs (<500 Da) have been the molecular class of choice for intracellular target drug development due to their good stability, oral bioavailability, and transmembrane ability. For example, the small molecule drug navitoclax targeting PPI can enter cells and bind tightly to the anti-apoptotic protein BCL-2, blocking the interaction between BCL-2 and the pro-apoptotic protein BAK/BAX, thereby promoting apoptosis. Although the regulation of PPI interaction by small molecules is relatively general for target localization, it also has its shortcomings. Because the interface surface area of PPI interaction is often large (about 1000-3000 Å^2), and the interaction interface of PPI is relatively flat, it is difficult for small molecules and proteins to bind, with low affinity and poor druggability.