Design of dual-effect molecules based on lysosome-targeting strategy: a mechanistic study on synergistic inhibition of ewing sarcoma and coronaviruses.

INTRODUCTION: Addressing clinical challenges such as the toxicity of conventional chemotherapy and viral drug resistance, this study proposes and validates an innovative "host organelle-targeting" strategy. By disrupting the function of host lysosomes-an organelle commonly exploited by both tumors and viruses-we aim to develop novel therapeutic agents with dual antitumor and antiviral activity.

METHODS: We rationally designed and synthesized the target compound 3-chloro-4-(4-(diethylamino)butoxy)benzaldehyde, whose core design relies on the pH-responsive property of the 4-(diethylamino)butoxy side chain to enable specific enrichment within the acidic lumen of lysosomes. In vitro activity was evaluated against Ewing sarcoma cells (TC32), prostate cancer bone metastasis model cells, porcine epidemic diarrhea virus (PEDV), and transmissible gastroenteritis virus (TGEV). Mechanistic investigations assessed lysosomal pH, autophagic flux, endoplasmic reticulum stress-related gene expression, p53 signaling pathway, cell cycle, and apoptosis.

RESULTS: The compound potently inhibited the proliferation of TC32 cells (IC50 = 25 μM) and prostate cancer bone metastasis cells, and significantly suppressed the replication of PEDV and TGEV. Mechanistic studies revealed that the compound neutralizes lysosomal pH, impairs acidification, blocks autophagic flux, upregulates endoplasmic reticulum stress-related gene expression, activates the p53 signaling pathway, and inhibits the cell cycle, ultimately leading to apoptosis.

CONCLUSION: This study reports a chemical entity with well-defined dual antitumor and antiviral activities and provides mechanistic evidence supporting the feasibility of the "host-lysosome targeting" strategy. It thus offers an important proof-of-concept and a research framework for developing broad-spectrum host-directed therapies.