A peptide targeting p21-CDK4 interaction for treatment of pulmonary fibrosis

forthcoming

Pulmonary fibrosis is an age-related disease characterized by progressive scarring of lung tissue, loss of respiratory function, and premature death. It is a fatal disease, affecting roughly ~5 million worldwide and causing >17.000 annual deaths in Europe alone. There is no cure for pulmonary fibrosis, as current treatments modestly slow disease progression but do not reverse fibrosis or substantially improve survival. These therapies often carry significant side effects and fail to address the underlying drivers of the disease, namely, the accumulation of senescent cells and ECM production. To meet this urgent unmet medical need, we propose a novel therapeutic strategy that selectively targets a key protein-protein interaction driving fibrosis. We discovered that the interaction between p21 and CDK4 is critical for both the survival of senescent cells and the regulation of ECM components. Disrupting this interaction mimics the effects of p21 knockdown, which we have shown eliminates senescent cells and limits fibrosis. Based on this insight, we designed and tested synthetic peptides that bind to CDK4 and block its interaction with p21. Several of these peptides show strong binding and selective senolytic activity in vitro, demonstrating precise modulation of this novel target and offering a promising strategy for an incurable disease. Our PoC project will advance this innovation toward therapeutic application. Specifically, we aim to identify a lead peptide with low micromolar potency and test its efficacy in a preclinical mouse model of pulmonary fibrosis, thereby reaching TRL4. This work lays the foundation for a highly specific, well-tolerated, and potentially curative treatment that addresses the root mechanisms of fibrosis rather than its symptoms alone. By targeting a previously unexplored molecular pathway, our approach offers new hope for millions affected by fibrotic lung diseases and could extend to broader applications in age-related fibrotic conditions.