Human-Based Immune Responsive In Vitro Infection Models for Validation of Novel TLR4 Antagonists Identified by Computational Discovery
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. Pro...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-01-01
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| Series: | Microorganisms |
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| Online Access: | https://www.mdpi.com/2076-2607/10/2/243 |
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| author | Helena Merk Tehila Amran-Gealia Doris Finkelmeier Christina Kohl Isabelle Pichota Noa Stern Steffen Rupp Amiram Goldblum Anke Burger-Kentischer |
| author_facet | Helena Merk Tehila Amran-Gealia Doris Finkelmeier Christina Kohl Isabelle Pichota Noa Stern Steffen Rupp Amiram Goldblum Anke Burger-Kentischer |
| author_sort | Helena Merk |
| collection | DOAJ |
| description | 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 <i>Candida albicans</i> 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. |
| first_indexed | 2024-03-09T21:24:47Z |
| format | Article |
| id | doaj.art-8833d68186f14e6eb8af7f03152948a2 |
| institution | Directory Open Access Journal |
| issn | 2076-2607 |
| language | English |
| last_indexed | 2024-03-09T21:24:47Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Microorganisms |
| spelling | doaj.art-8833d68186f14e6eb8af7f03152948a22023-11-23T21:13:05ZengMDPI AGMicroorganisms2076-26072022-01-0110224310.3390/microorganisms10020243Human-Based Immune Responsive In Vitro Infection Models for Validation of Novel TLR4 Antagonists Identified by Computational DiscoveryHelena Merk0Tehila Amran-Gealia1Doris Finkelmeier2Christina Kohl3Isabelle Pichota4Noa Stern5Steffen Rupp6Amiram Goldblum7Anke Burger-Kentischer8Institute of Interfacial Process Engineering and Plasma Technology, University of Stuttgart, Nobelstr. 12, 70569 Stuttgart, GermanyLaboratory of Molecular Modelling, Faculty of Medicine, Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem 91120, IsraelFraunhofer Institute of Interfacial Engineering and Biotechnology IGB, Nobelstr. 12, 70569 Stuttgart, GermanyFraunhofer Institute of Interfacial Engineering and Biotechnology IGB, Nobelstr. 12, 70569 Stuttgart, GermanyFraunhofer Institute of Interfacial Engineering and Biotechnology IGB, Nobelstr. 12, 70569 Stuttgart, GermanyLaboratory of Molecular Modelling, Faculty of Medicine, Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem 91120, IsraelInstitute of Interfacial Process Engineering and Plasma Technology, University of Stuttgart, Nobelstr. 12, 70569 Stuttgart, GermanyLaboratory of Molecular Modelling, Faculty of Medicine, Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem 91120, IsraelFraunhofer Institute of Interfacial Engineering and Biotechnology IGB, Nobelstr. 12, 70569 Stuttgart, GermanyInfectious 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 <i>Candida albicans</i> 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.https://www.mdpi.com/2076-2607/10/2/2433D-immune-competent Infection models<i>Candida albicans</i>Toll-like receptorsantagonistpharmacophoredocking |
| spellingShingle | Helena Merk Tehila Amran-Gealia Doris Finkelmeier Christina Kohl Isabelle Pichota Noa Stern Steffen Rupp Amiram Goldblum Anke Burger-Kentischer Human-Based Immune Responsive In Vitro Infection Models for Validation of Novel TLR4 Antagonists Identified by Computational Discovery Microorganisms 3D-immune-competent Infection models <i>Candida albicans</i> Toll-like receptors antagonist pharmacophore docking |
| title | Human-Based Immune Responsive In Vitro Infection Models for Validation of Novel TLR4 Antagonists Identified by Computational Discovery |
| title_full | Human-Based Immune Responsive In Vitro Infection Models for Validation of Novel TLR4 Antagonists Identified by Computational Discovery |
| title_fullStr | Human-Based Immune Responsive In Vitro Infection Models for Validation of Novel TLR4 Antagonists Identified by Computational Discovery |
| title_full_unstemmed | Human-Based Immune Responsive In Vitro Infection Models for Validation of Novel TLR4 Antagonists Identified by Computational Discovery |
| title_short | Human-Based Immune Responsive In Vitro Infection Models for Validation of Novel TLR4 Antagonists Identified by Computational Discovery |
| title_sort | human based immune responsive in vitro infection models for validation of novel tlr4 antagonists identified by computational discovery |
| topic | 3D-immune-competent Infection models <i>Candida albicans</i> Toll-like receptors antagonist pharmacophore docking |
| url | https://www.mdpi.com/2076-2607/10/2/243 |
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