Merk Helena, Amran-Gealia Tehila, Finkelmeier Doris, Kohl Christina, Pichota Isabelle, Stern Noa, Rupp Steffen, Goldblum Amiram, Burger-Kentischer Anke
Institute of Interfacial Process Engineering and Plasma Technology, University of Stuttgart, Nobelstr. 12, 70569 Stuttgart, Germany.
Laboratory of Molecular Modelling, Faculty of Medicine, Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
Microorganisms. 2022 Jan 22;10(2):243. doi: 10.3390/microorganisms10020243.
Infectious diseases are still a major problem worldwide. This includes microbial infections, with a constant increase in resistance to the current anti-infectives employed. Toll-like receptors (TLRs) perform a fundamental role in pathogen recognition and activation of the innate immune response. Promising new approaches to combat infections and inflammatory diseases involve modulation of the host immune system via TLR4. TLR4 and its co-receptors MD2 and CD14 are required for immune response to fungal and bacterial infection by recognition of microbial cell wall components, making it a prime target for drug development. To evaluate the efficacy of anti-infective compounds early on, we have developed a series of human-based immune responsive infection models, including immune responsive 3D-skin infection models for modeling fungal infections. By using computational methods: pharmacophore modeling and molecular docking, we identified a set of 46 potential modulators of TLR4, which were screened in several tests systems of increasing complexity, including immune responsive 3D-skin infection models. We could show a strong suppression of cytokine and chemokine response induced by lipopolysacharide (LPS) and for individual compounds. The development of human-based immune responsive assays provides a more accurate and reliable basis for development of new anti-inflammatory or immune-modulating drugs.
传染病仍是全球范围内的一个主要问题。这包括微生物感染，且对目前使用的抗感染药物的耐药性不断增加。Toll样受体（TLRs）在病原体识别和先天免疫反应激活中发挥着重要作用。通过TLR4调节宿主免疫系统是对抗感染和炎症性疾病的有前景的新方法。TLR4及其共受体MD2和CD14通过识别微生物细胞壁成分，对真菌和细菌感染的免疫反应是必需的，这使其成为药物开发的主要靶点。为了尽早评估抗感染化合物的疗效，我们开发了一系列基于人体的免疫反应性感染模型，包括用于模拟真菌感染的免疫反应性3D皮肤感染模型。通过使用计算方法：药效团建模和分子对接，我们确定了一组46种潜在的TLR4调节剂，并在包括免疫反应性3D皮肤感染模型在内的几个复杂性不断增加的测试系统中进行了筛选。我们可以证明，对于个别化合物，脂多糖（LPS）诱导的细胞因子和趋化因子反应受到强烈抑制。基于人体的免疫反应性检测方法的开发为新型抗炎或免疫调节药物的开发提供了更准确可靠的基础。
