arXiv:2606.27824cs.LGcs.AI2026-06

让肽段生成避开毒性区域,高效设计安全靶向肽

Pepti-drift: Toxicity-Repulsive Drifting for Antigen-Conditioned Discrete Peptide Generation

论文配图:Pepti-drift: Toxicity-Repulsive Drifting for Antigen-Conditioned Discrete Peptide Generation
图 1 · 摘自论文原文
  • 通过吸引结合肽、排斥毒性肽的双向优化生成
  • 速度比现有方法快1092倍,生成肽100%有效且多样
  • 适合需要安全高活性肽段的药物研发人员

肽类是兼具小分子可修饰性与大分子靶向特异性的有前景治疗手段。但设计靶向抗原且无毒的肽仍是一大挑战。本文提出Pepti-drift,一种毒性感知的潜在空间精炼框架,仅通过一次抗原条件漂移即可生成候选肽。在肽嵌入空间中,该方法学习将生成肽的潜在表示吸引至抗原匹配的结合肽区域,同时排斥至与毒性相关的区域。由于促进结合的理化特征常与毒性特征重叠,为此我们引入热启动策略:先学习以结合为导向的吸引,再逐步增强毒性排斥。Pepti-drift在效率上远超现有方法——比PepMLM快16.2倍,比PepTune快1092.0倍。生成肽序列100%有效,98.1%唯一,序列多样性最高,跨抗原重复率接近零。评估显示,在多数长度范围内均显著降低毒性与溶血风险,同时保持目标结合预测信号。Pepti-drift为靶向肽设计提供了一种快速、可扩展且可控的框架,直接编码安全与活性属性。

原文摘要 · Abstract (English)

Peptides are a promising therapeutic modality that combine the chemical tunability of small molecules with the target specificity of macromolecular therapeutics. However, designing antigen-specific binding peptides while avoiding toxicity remains a major challenge for therapeutic peptide discovery. Here, we present Pepti-drift, a toxicity-aware latent refinement framework that generates peptide candidates through a single antigen-conditioned drift step. In a peptide embedding space, Pepti-drift learns to attract generated peptide latents toward antigen-matched binding peptides while repelling them from toxicity-associated regions. This is challenging because binding-promoting physicochemical features often overlap with toxicity-associated features in peptide representation space. To address this, we introduce a warm-up strategy to stabilize this competing objective by first learning binding-oriented attraction and then increasing toxicity repulsion. Pepti-drift achieves highly efficient generation, running 16.2-fold faster than PepMLM and 1,092.0-fold faster than PepTune. Generated peptides show 100% validity, 98.1% uniqueness, the highest sequence diversity, and near-zero cross-antigen reuse. Further evaluation indicates consistently reduced toxicity and hemolysis risk across most peptide-length ranges while retaining target-related predictive binding signal. Pepti-drift thus provides a fast, scalable, and controllable framework for antigen-specific peptide design that directly encodes safe-and-active properties.

肽生成毒性规避生成模型药物设计

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