Das CeMM - Forschungszentrum für Molekulare Medizin GmbH

尽管过去几年蛋白质结构预测取得了重大进展，但鉴定大多数蛋白质的小分子配体仍然具有挑战性。4月26日，辉瑞与来自奥地利CeMM的科学家们在Science杂志发表一项突破性成果。经过过去3年的合作，他们扩展了一种方法来测定数百种小分子与数千种人类蛋白质的结合活性，这项大规模研究揭示了约50,000种配体-蛋白质相互作用。同时，该研究还开发出了一款人工智能（AI）模型，可以预测小分子如何与活的人类细胞中表达的蛋白质相互作用。目前来说，大多数药物都是调节蛋白活性的小分子，且小分子也是进行基础生物学研究的宝贵工具。然而，目前为止，大约80%的人类蛋白质组仍缺乏功能性配体，这是药物研发的重大障碍。在该研究中，科学家们利用化学蛋白质组学方法来绘制人类蛋白质组中的蛋白质与配体的相互作用。研究确定了407个结构多样的小分子片段的相互作用组（interactome），鉴定出了47,658种小分子片段-蛋白质相互作用，涉及2600多种蛋白质，其中86%先前缺乏配体（annotated ligand）。发现SLC29A1抑制剂基于这些数据，研究者们进一步开发了招募E3连接酶衔接蛋白DDB1的配体、阻断SLC29A1的配体以及选择性抑制一部分细胞周期蛋白依赖激酶（包括CDK16）的受体，进而证明了这些数据的转化潜力。更值得一提的是，利用相关数据集，科学家们还开发了一个机器学习框架来构建模型，以预测其他小分子/片段如何与蛋白质组范围内的天然蛋白相互作用。这些重要进展将加快迄今为止尚未成药的蛋白质的配体发现工作。蛋白-配体相互作用特征的鉴定与预测CeMM领导该研究的 Georg Winter博士表示：“我们希望该小分子-蛋白质相互作用目录及相关的人工智能（AI）模型能够为药物研发提供一条捷径。” 值得一提的是，该研究中所有生成的数据和模型均免费向科学界开放（https://ligand-discovery.ai）。“这是一个伟大的项目，也是工业界和学术界之间的一次杰出合作。”辉瑞副总裁兼药物设计负责人Patrick Verhoest博士说道。备注：文中图片均来自Science。参考资料：[1]https://www.science.org/doi/10.1126/science.adk5864[2]https://www.cemm.at/news/n/a-shortcut-for-drug-discovery-novel-method-predicts-on-a-large-scale-how-small-molecules-interact-with-proteins[3]https://www.fiercebiotech.com/research/pfizer-collab-austrian-research-institute-leads-new-ai-models-drug-discovery推荐阅读1天2篇Nature！“合成致死”靶点WRN，抗癌潜力无限蛋白降解技术盘点：LYTAC、ATAC、AbTAC、PROTAB、REULR、KineTAC、IFLD……Copyright © 2024 PHARMCUBE. All Rights Reserved.欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任。

Hitherto, scientists have not fully understood why ticks are such dangerous disease vectors. A research team now shows that tick saliva inhibits the skin's defense function, thereby increasing the risk of diseases such as tick-borne encephalitis (TBE) or Lyme disease. Hitherto, scientists have not fully understood why ticks are such dangerous disease vectors. A research team led by Johanna Strobl and Georg Stary from MedUni Vienna's Department of Dermatology shows that tick saliva inhibits the skin's defence function, thereby increasing the risk of diseases such as tick-borne encephalitis (TBE) or Lyme disease. The study was recently published in the Journal of Clinical Investigation. The researchers carried out their investigations on skin samples from volunteers and also on models of human skin, mimicking the bite of the most common European tick (Ixodes ricinus). In both cases, the team led by Georg Stary (MedUni Vienna's Department of Dermatology, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases) in collaboration with the research group of Hannes Stockinger (Center for Pathophysiology, Infectiology and Immunology at MedUni Vienna) identified rapidly occurring patterns of immunomodulation. For example, it was found that the function of immune cells, especially T cells, which are important for immunological memory, was disrupted by contact with tick saliva. Tick saliva modulates immune system The scientists made similar observations in early stages of model infection by Borrelia burgdorferi, the most common cause of Lyme disease. They found that pre-incubation of Lyme disease-transmitting bacteria (B. burgdorferi spirochetes) with tick salivary gland extracts impedes the accumulation of immune cells in the skin and increases the pathogen burden. "Overall, we found that tick feeding causes profound changes in the skin's immune system inhibiting the local immune response. This means that dangerous pathogens that are introduced into the skin together with tick saliva, can multiply more easily, leading to infection," says Johanna Strobl, lead author of the study, summarising the main research findings. Climate change increases danger from ticks Austria is one of the countries with the greatest prevalence of ticks. Nearly every second European tick is infected with pathogens, Lyme disease and tick-borne encephalitis (TBE) being the most common tick-borne diseases. The arachnids become active at a temperature of seven degrees. Due to rising temperatures associated with climate change, ticks now also pose a threat in higher-altitude regions of Austria and well into late autumn.