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Design of Inhibitory Peptides Based on TRPM4-KCTD5 Interaction

Javiera Baeza1,2, Diego Maureira1, Mariela Gonzalez-Avendaño2

  • 1Núcleo Interdisciplinario de Biología y Genética, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago8380453, Chile.

Journal of Chemical Information and Modeling
|May 29, 2026
PubMed

Insights

Researchers designed peptides to block the TRPM4-KCTD5 interaction, a key driver in metastatic breast cancer. These peptides successfully reduced cancer cell invasion, offering a potential new therapeutic strategy.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Transient Receptor Potential Melastatin 4 (TRPM4) channels are implicated in cytoskeletal rearrangement and cell migration, contributing to pathologies like fibrosis and metastatic cancer.
  • KCTD5 acts as a positive regulator of TRPM4, enhancing its calcium (Ca2+) sensitivity and influencing cell migration.
  • Elevated TRPM4 and KCTD5 expression correlates with poor prognosis in breast cancer, identifying their interaction as a potential therapeutic target.

Purpose of the Study:

  • To design and evaluate peptides targeting the TRPM4-KCTD5 protein-protein interaction.
  • To assess the therapeutic potential of these peptides in inhibiting TRPM4 activity and reducing cancer cell invasion.

Main Methods:

  • In silico peptide design based on the TRPM4-KCTD5 interface.
  • In vitro assays including bimolecular fluorescent complementation (BiFC), patch clamp electrophysiology, and intracellular sodium recordings.
  • Cell invasion assays using MDA-MB-231 breast cancer cells.

Main Results:

  • Designed peptides (TAT-TRPM4-HA, TAT-KCTD5-HA) disrupted the TRPM4-KCTD5 interaction, as shown by reduced BiFC signal.
  • Peptide treatment significantly decreased TRPM4-dependent sodium (Na+) influx and ion channel currents in HEK293 cells.
  • The TAT-TRPM4-HA peptide notably reduced cell invasion in MDA-MB-231 breast cancer cells.

Conclusions:

  • The developed peptides effectively inhibit the TRPM4-KCTD5 interaction.
  • Targeting the TRPM4-KCTD5 interface with peptides shows promise for reducing metastatic breast cancer cell invasion.
  • The TRPM4-KCTD5 interaction represents a viable therapeutic target for metastatic breast cancer treatment.

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