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<p>Developing targeted cancer therapies with high selectivity, low toxicity, and cost-effectiveness remains a major challenge in modern medicine. This study aimed to design a Gallocin-derived anticancer peptide (ACP) targeting the epidermal growth factor receptor (EGFR) using an integrated bioinformatics and experimental approach. Gallocin, a bacteriocin from <i>Streptococcus gallolyticus</i>, was selected for its unique four α-helix structure and anticancer motifs, making it a promising candidate for ACP in initial in silico analysis. The Gallocin-derived ACPs were predicted using web-based tools. Molecular docking studies assessed the binding affinity of ACPs to EGFR, and molecular dynamics simulations analyzed the stability of the Galcn-1-EGFR complex. The absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis evaluated pharmacokinetic properties. Docking revealed that Galcn-1 had a high binding affinity for EGFR, forming stable hydrogen bonds. Molecular dynamics simulations confirmed complex stability. Experimental validation showed that Galcn-1 exhibited an IC₅₀ of 16&#xa0;µg/ml in HT-29 cells. Galcn-1 downregulated <i>EGFR</i> and <i>PI3K</i> expression, induced apoptosis via both extrinsic (<i>CAS-8</i>) and intrinsic (<i>CAS-9</i>) pathways, increased ROS production, and caused cell cycle arrest in the S-phase. Pharmacokinetic evaluations indicated improved metabolism and lower toxicity, along with decreased permeability and a shorter half-life. Future optimization through bioengineering, such as peptide conjugation and chemical modifications (PEGylation), use of a synthetic staple, and development of drug delivery systems, will enhance stability, protect the peptide from proteolytic degradation, extend its half-life and binding affinity, and improve permeability and function, positioning Galcn-1 for further preclinical and clinical development.</p>

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From Bacteria to Breakthroughs: Design and Evaluation of Gallocin-Based Peptide for Colorectal Cancer Therapeutic

  • 期刊论文

  • 发表日期：

    2026年5月30日

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  • Batoul Kavyani,
  • Fereshteh Saffari,
  • Ali Afgar,
  • Ehsan Salarkia,
  • Alireza Keyhani,
  • Sajjad Kavyani,
  • Masoud Rezaie,
  • Fatemeh Sharifi,
  • Roya Ahmadrajabi

摘要

Developing targeted cancer therapies with high selectivity, low toxicity, and cost-effectiveness remains a major challenge in modern medicine. This study aimed to design a Gallocin-derived anticancer peptide (ACP) targeting the epidermal growth factor receptor (EGFR) using an integrated bioinformatics and experimental approach. Gallocin, a bacteriocin from Streptococcus gallolyticus, was selected for its unique four α-helix structure and anticancer motifs, making it a promising candidate for ACP in initial in silico analysis. The Gallocin-derived ACPs were predicted using web-based tools. Molecular docking studies assessed the binding affinity of ACPs to EGFR, and molecular dynamics simulations analyzed the stability of the Galcn-1-EGFR complex. The absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis evaluated pharmacokinetic properties. Docking revealed that Galcn-1 had a high binding affinity for EGFR, forming stable hydrogen bonds. Molecular dynamics simulations confirmed complex stability. Experimental validation showed that Galcn-1 exhibited an IC₅₀ of 16 µg/ml in HT-29 cells. Galcn-1 downregulated EGFR and PI3K expression, induced apoptosis via both extrinsic (CAS-8) and intrinsic (CAS-9) pathways, increased ROS production, and caused cell cycle arrest in the S-phase. Pharmacokinetic evaluations indicated improved metabolism and lower toxicity, along with decreased permeability and a shorter half-life. Future optimization through bioengineering, such as peptide conjugation and chemical modifications (PEGylation), use of a synthetic staple, and development of drug delivery systems, will enhance stability, protect the peptide from proteolytic degradation, extend its half-life and binding affinity, and improve permeability and function, positioning Galcn-1 for further preclinical and clinical development.