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Targeting ClpP Protease: Emerging Therapeutic Strategies and Small-Molecule Modulators in Drug Discovery
Lihua Liu1, Minghui Yu1, Xinnan Li1
1Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
Medicinal Research Reviews
|May 21, 2026
Summary
Caseinolytic protease P (ClpP) is crucial for protein quality control and cellular homeostasis. New ClpP modulators show promise for targeted protein degradation in antibacterial and anticancer therapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- The caseinolytic protease P (ClpP) is a conserved serine protease essential for protein quality control and homeostasis across diverse organisms.
- ClpP functions with AAA+ chaperones, playing roles in proteostasis, metabolic balance, stress responses, and bacterial virulence.
- The human ClpP and ClpX complex (hClpXP) is increasingly recognized for its relevance in human diseases.
Purpose of the Study:
- To review current knowledge of ClpP architecture and regulatory mechanisms.
- To emphasize ClpP's roles in cellular homeostasis and pathophysiology.
- To highlight advances in small-molecule ClpP modulators for therapeutic applications.
Main Methods:
- Review of existing literature on ClpP structure, function, and regulation.
- Analysis of small-molecule ClpP modulators, including activators, inhibitors, and PROTACs.
- Discussion of therapeutic strategies targeting ClpP for antibacterial and anticancer drug discovery.
Main Results:
- ClpP's tetradecameric structure and gating enable selective substrate recognition, unfolding, and proteolysis.
- Small-molecule modulators, including BacPROTACs and MtPTACs, harness ClpP for targeted protein degradation.
- Challenges include achieving selectivity between bacterial and human ClpP and minimizing off-target effects.
Conclusions:
- ClpP-directed therapeutics offer a promising strategy for next-generation antibacterial and anticancer drug discovery.
- Further research is needed to overcome challenges in selectivity, off-target effects, and resistance.
- Designing reversible covalent inhibitors and novel allosteric modulators presents future opportunities.
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