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<p>Conotoxins are small, disulfide-rich peptides that display exceptional affinity and selectivity for ion channels and receptors, making them valuable templates for therapeutic development. However, their optimization remains challenging due to the limited diversity of naturally occurring variants and the labor-intensive nature of conventional engineering strategies. Here, we present CreoPep, a deep learning-based generative framework specifically developed to design and optimize conotoxins targeting defined receptors. CreoPep integrates masked language modeling with a progressive masking scheme and employs an augmentation pipeline that combines physics-based energy screening with temperature-controlled multinomial sampling. This enables the generation of structurally and functionally diverse peptide variants while retaining essential pharmacological features. Structural analysis shows that CreoPep-generated variants adopt both conserved and previously unobserved binding modes, including disulfide-deficient forms. Together, these findings establish CreoPep as a powerful computational-experimental framework for the rational design of conotoxin-based peptides and provide a foundation for extending similar approaches to other peptide families.</p>

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A deep learning framework (CreoPep) for target-specific design and optimization of conotoxin peptides

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月9日

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  • Cheng Ge,
  • Han-Shen Tae,
  • Lu Lu,
  • Zhenqiang Zhang,
  • Zhijie Huang,
  • Baixue An,
  • Yilin Wang,
  • Tao Jiang,
  • Wenqing Cai,
  • Shan Chang,
  • David J. Adams,
  • Rilei Yu

摘要

Conotoxins are small, disulfide-rich peptides that display exceptional affinity and selectivity for ion channels and receptors, making them valuable templates for therapeutic development. However, their optimization remains challenging due to the limited diversity of naturally occurring variants and the labor-intensive nature of conventional engineering strategies. Here, we present CreoPep, a deep learning-based generative framework specifically developed to design and optimize conotoxins targeting defined receptors. CreoPep integrates masked language modeling with a progressive masking scheme and employs an augmentation pipeline that combines physics-based energy screening with temperature-controlled multinomial sampling. This enables the generation of structurally and functionally diverse peptide variants while retaining essential pharmacological features. Structural analysis shows that CreoPep-generated variants adopt both conserved and previously unobserved binding modes, including disulfide-deficient forms. Together, these findings establish CreoPep as a powerful computational-experimental framework for the rational design of conotoxin-based peptides and provide a foundation for extending similar approaches to other peptide families.