Targeting ClpP Protease: Emerging Therapeutic Strategies and Small‐Molecule Modulators in Drug Discovery

The caseinolytic protease P (ClpP) is a conserved serine protease that functions with ATPases associated with diverse cellular activities (AAA+) chaperones to ensure protein quality control in organisms ranging from bacteria to human mitochondria. Its tetradecameric structure and adjustable gating support selective substrate recognition, unfolding, and proteolysis, thereby contributing to proteostasis, metabolic balance, stress responses, and bacterial virulence. Growing insights into human ClpP and ClpX complex (hClpXP) have further underscored its relevance to human disease. This review summarizes current knowledge of ClpP architecture and regulatory mechanisms, with emphasis on its roles in cellular homeostasis and pathophysiology. We highlight advances in small-molecule ClpP modulators, including activators, inhibitors, and emerging heterobifunctional degraders such as bacterial proteolysis-targeting chimeras (BacPROTACs) and mitochondrial-targeted PROTACs (MtPTACs), which harness ClpP activity for targeted protein degradation in antibacterial and anticancer applications. Despite notable progress, challenges remain, particularly in achieving selectivity between bacterial and human ClpP (hClpP), minimizing off-target effects, and preventing resistance. Future opportunities include designing reversible covalent inhibitors, developing novel allosteric modulators, and optimizing degrader architectures to expand therapeutic potential. ClpP-directed therapeutic strategies therefore represent a promising avenue for next-generation antibacterial and anticancer drug discovery.