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Design of dual-effect molecules based on lysosome-targeting strategy: a mechanistic study on synergistic inhibition

Shimeng Zhou1, Lu Xu2, Wenlong Ge1

  • 1Cangzhou Integrated Traditional Chinese and Western Medicine Hospital, Hebei Key Laboratory of Integrated Traditional and Western Medicine in Osteoarthrosis Research (Preparing), Cangzhou, Hebei, China.

Frontiers in Chemistry
|July 9, 2026
PubMed
Abstract

Insights

This study introduces a novel strategy targeting host lysosomes to create dual-action drugs effective against cancer and viruses. The developed compound disrupts lysosomal function, offering a new approach for broad-spectrum therapies.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Conventional chemotherapy faces challenges with toxicity and viral drug resistance.
  • Tumors and viruses exploit host cell lysosomes for their survival and replication.
  • There is a need for novel therapeutic agents with broad-spectrum activity.

Purpose of the Study:

  • To propose and validate a "host organelle-targeting" strategy using lysosomes.
  • To develop novel therapeutic agents with dual antitumor and antiviral activity.
  • To investigate the mechanism of action of a rationally designed compound targeting host lysosomes.

Main Methods:

  • Designed and synthesized a pH-responsive compound, 3-chloro-4-(4-(diethylamino)butoxy)benzaldehyde.
  • Evaluated in vitro activity against Ewing sarcoma cells, prostate cancer cells, porcine epidemic diarrhea virus (PEDV), and transmissible gastroenteritis virus (TGEV).
  • Conducted mechanistic investigations including lysosomal pH, autophagic flux, endoplasmic reticulum stress, p53 signaling, cell cycle, and apoptosis.

Main Results:

  • The compound demonstrated potent inhibition of cancer cell proliferation (IC50 = 25 μM for TC32 cells).
  • Significant suppression of PEDV and TGEV replication was observed.
  • Mechanistic studies showed lysosomal pH neutralization, impaired acidification, blocked autophagic flux, upregulated ER stress, activated p53 signaling, and cell cycle inhibition leading to apoptosis.

Conclusions:

  • A chemical entity with dual antitumor and antiviral activities was identified.
  • Mechanistic evidence supports the "host-lysosome targeting" strategy.
  • This study provides a proof-of-concept and framework for developing broad-spectrum host-directed therapies.
Keywords:
HostorganelletargetingLysosometargetingantitumorantiviraldual activity

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