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生成式潜在扩散语言建模产生抗感染合成肽。

Generative latent diffusion language modeling yields anti-infective synthetic peptides.

作者信息

Torres Marcelo D T, Chen Tianlai, Wan Fangping, Chatterjee Pranam, de la Fuente-Nunez Cesar

机构信息

Machine Biology Group, Departments of Psychiatry and Microbiology, Institute for Biomedical Informatics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

Departments of Bioengineering and Chemical and Biomolecular Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

出版信息

bioRxiv. 2025 Feb 1:2025.01.31.636003. doi: 10.1101/2025.01.31.636003.

Abstract

Generative artificial intelligence (AI) offers a powerful avenue for peptide design, yet this process remains challenging due to the vast sequence space, complex structure-activity relationships, and the need to balance antimicrobial potency with low toxicity. Traditional approaches often rely on trial-and-error screening and fail to efficiently navigate the immense diversity of potential sequences. Here, we introduce AMP-Diffusion, a novel latent diffusion model fine-tuned on antimicrobial peptide (AMP) sequences using embeddings from protein language models. By systematically exploring sequence space, AMP-Diffusion enables the rapid discovery of promising antibiotic candidates. We generated 50,000 candidate sequences, which were subsequently filtered and ranked using our APEX predictor model. From these, 46 top candidates were synthesized and experimentally validated. The resulting AMP-Diffusion peptides demonstrated broad-spectrum antibacterial activity, targeting clinically relevant pathogens-including multidrug-resistant strains-while exhibiting low cytotoxicity in human cell assays. Mechanistic studies revealed bacterial killing via membrane permeabilization and depolarization, and the peptides showed favorable physicochemical profiles. In preclinical mouse models of infection, lead peptides effectively reduced bacterial burdens, displaying efficacy comparable to polymyxin B and levofloxacin, with no detectable adverse effects. This study highlights the potential of AMP-Diffusion as a robust generative platform for designing novel antibiotics and bioactive peptides, offering a promising strategy to address the escalating challenge of antimicrobial resistance.

摘要

生成式人工智能为肽设计提供了一条有力途径,但由于序列空间巨大、结构-活性关系复杂,以及需要在抗菌效力和低毒性之间取得平衡,这一过程仍然具有挑战性。传统方法通常依赖试错筛选,无法有效地在潜在序列的巨大多样性中进行筛选。在这里,我们介绍了AMP-Diffusion,这是一种新颖的潜在扩散模型,它使用来自蛋白质语言模型的嵌入对抗菌肽(AMP)序列进行了微调。通过系统地探索序列空间,AMP-Diffusion能够快速发现有前景的抗生素候选物。我们生成了50000个候选序列,随后使用我们的APEX预测模型进行过滤和排名。从中合成并实验验证了46个顶级候选物。所得的AMP-Diffusion肽表现出广谱抗菌活性,针对包括多重耐药菌株在内的临床相关病原体,同时在人类细胞试验中表现出低细胞毒性。机制研究揭示了通过膜通透性和去极化导致细菌死亡,并且这些肽表现出良好的物理化学性质。在临床前感染小鼠模型中,先导肽有效地降低了细菌载量,显示出与多粘菌素B和左氧氟沙星相当的疗效,且未检测到不良反应。这项研究突出了AMP-Diffusion作为设计新型抗生素和生物活性肽的强大生成平台的潜力,为应对日益严峻的抗菌耐药性挑战提供了一种有前景的策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d644/11838489/1bcea7e2e560/nihpp-2025.01.31.636003v1-f0001.jpg

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