New insights into protein–protein interaction modulators in drug discovery and therapeutic advance

Protein-protein interactions (PPIs) are fundamental to cellular signaling and transduction which marks them as attractive therapeutic drug development targets. What were once considered to be undruggable targets have become increasingly feasible due to the progress that has been made over the last two decades and the rapid technological advances. This work explores the influence of technological innovations on PPI research and development. Additionally, the diverse strategies for discovering, modulating, and characterizing PPIs and their corresponding modulators are examined with the aim of presenting a streamlined pipeline for advancing PPI-targeted therapeutics. By showcasing carefully selected case studies in PPI modulator discovery and development, we aim to illustrate the efficacy of various strategies for identifying, optimizing, and overcoming challenges associated with PPI modulator design. The valuable lessons and insights gained from the identification, optimization, and approval of PPI modulators are discussed with the aim of demonstrating that PPI modulators have transitioned beyond early-stage drug discovery and now represent a prime opportunity with significant potential. The selected examples of PPI modulators encompass those developed for cancer, inflammation and immunomodulation, as well as antiviral applications. This perspective aims to establish a foundation for the effective targeting and modulation of PPIs using PPI modulators and pave the way for future drug development.