Massively Parallel Screening of Toll/Interleukin‐1 Receptor (TIR)‐Derived Peptides Reveals Multiple Toll‐Like Receptors (TLRs)‐Targeting Immunomodulatory Peptides
Abstract Toll‐like receptors (TLRs) are critical regulators of the immune system, and altered TLR responses lead to a variety of inflammatory diseases. Interference of intracellular TLR signaling, which is mediated by multiple Toll/interleukin‐1 receptor (TIR) domains on all TLRs and TLR adapters, i...
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Wiley
2025-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202406018 |
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| author | Yun Lim Tae Kyeom Kang Meong Il Kim Dohyeon Kim Ji Yul Kim Sang Hoon Jung Keunwan Park Wook‐Bin Lee Moon‐Hyeong Seo |
| author_facet | Yun Lim Tae Kyeom Kang Meong Il Kim Dohyeon Kim Ji Yul Kim Sang Hoon Jung Keunwan Park Wook‐Bin Lee Moon‐Hyeong Seo |
| author_sort | Yun Lim |
| collection | DOAJ |
| description | Abstract Toll‐like receptors (TLRs) are critical regulators of the immune system, and altered TLR responses lead to a variety of inflammatory diseases. Interference of intracellular TLR signaling, which is mediated by multiple Toll/interleukin‐1 receptor (TIR) domains on all TLRs and TLR adapters, is an effective therapeutic strategy against immune dysregulation. Peptides that inhibit TIR‐TIR interactions by fragmenting interface residues have potential as therapeutic decoys. However, a systematic method for discovering TIR‐targeting moieties has been elusive, limiting exploration of the vast, unsequenced space of the TIR domain family. A comprehensive parallel screening method is developed to uncover novel TIR‐binding peptides derived from previously unexplored surfaces on a wide range of TIR domains. A large peptide library is constructed, named TIR surfacesome, by tiling surface sequences of the large TIR domain family and screening against MALTIR and MyD88TIR, TIRs of two major TLR adaptor proteins, resulting in the discovery of hundreds of TIR‐binding peptides. The selected peptides inhibited TLR signaling and demonstrated anti‐inflammatory effects in macrophages, and therapeutic potential in mouse inflammatory models. This approach may facilitate the development of TLR‐targeted therapeutics. |
| format | Article |
| id | doaj-art-37071de2dfee42f08ec8251fe4e105ed |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-37071de2dfee42f08ec8251fe4e105ed2025-01-09T11:44:45ZengWileyAdvanced Science2198-38442025-01-01121n/an/a10.1002/advs.202406018Massively Parallel Screening of Toll/Interleukin‐1 Receptor (TIR)‐Derived Peptides Reveals Multiple Toll‐Like Receptors (TLRs)‐Targeting Immunomodulatory PeptidesYun Lim0Tae Kyeom Kang1Meong Il Kim2Dohyeon Kim3Ji Yul Kim4Sang Hoon Jung5Keunwan Park6Wook‐Bin Lee7Moon‐Hyeong Seo8Natural Product Research Center Korea Institute of Science and Technology Gangneung 25451 Republic of KoreaNatural Product Research Center Korea Institute of Science and Technology Gangneung 25451 Republic of KoreaNatural Product Research Center Korea Institute of Science and Technology Gangneung 25451 Republic of KoreaNatural Product Informatics Research Center Korea Institute of Science and Technology Gangneung 25451 Republic of KoreaNatural Product Research Center Korea Institute of Science and Technology Gangneung 25451 Republic of KoreaNatural Product Research Center Korea Institute of Science and Technology Gangneung 25451 Republic of KoreaNatural Product Informatics Research Center Korea Institute of Science and Technology Gangneung 25451 Republic of KoreaNatural Product Research Center Korea Institute of Science and Technology Gangneung 25451 Republic of KoreaNatural Product Research Center Korea Institute of Science and Technology Gangneung 25451 Republic of KoreaAbstract Toll‐like receptors (TLRs) are critical regulators of the immune system, and altered TLR responses lead to a variety of inflammatory diseases. Interference of intracellular TLR signaling, which is mediated by multiple Toll/interleukin‐1 receptor (TIR) domains on all TLRs and TLR adapters, is an effective therapeutic strategy against immune dysregulation. Peptides that inhibit TIR‐TIR interactions by fragmenting interface residues have potential as therapeutic decoys. However, a systematic method for discovering TIR‐targeting moieties has been elusive, limiting exploration of the vast, unsequenced space of the TIR domain family. A comprehensive parallel screening method is developed to uncover novel TIR‐binding peptides derived from previously unexplored surfaces on a wide range of TIR domains. A large peptide library is constructed, named TIR surfacesome, by tiling surface sequences of the large TIR domain family and screening against MALTIR and MyD88TIR, TIRs of two major TLR adaptor proteins, resulting in the discovery of hundreds of TIR‐binding peptides. The selected peptides inhibited TLR signaling and demonstrated anti‐inflammatory effects in macrophages, and therapeutic potential in mouse inflammatory models. This approach may facilitate the development of TLR‐targeted therapeutics.https://doi.org/10.1002/advs.202406018age‐related macular degenerationpeptidessepsisTIR domainToll‐like receptors |
| spellingShingle | Yun Lim Tae Kyeom Kang Meong Il Kim Dohyeon Kim Ji Yul Kim Sang Hoon Jung Keunwan Park Wook‐Bin Lee Moon‐Hyeong Seo Massively Parallel Screening of Toll/Interleukin‐1 Receptor (TIR)‐Derived Peptides Reveals Multiple Toll‐Like Receptors (TLRs)‐Targeting Immunomodulatory Peptides Advanced Science age‐related macular degeneration peptides sepsis TIR domain Toll‐like receptors |
| title | Massively Parallel Screening of Toll/Interleukin‐1 Receptor (TIR)‐Derived Peptides Reveals Multiple Toll‐Like Receptors (TLRs)‐Targeting Immunomodulatory Peptides |
| title_full | Massively Parallel Screening of Toll/Interleukin‐1 Receptor (TIR)‐Derived Peptides Reveals Multiple Toll‐Like Receptors (TLRs)‐Targeting Immunomodulatory Peptides |
| title_fullStr | Massively Parallel Screening of Toll/Interleukin‐1 Receptor (TIR)‐Derived Peptides Reveals Multiple Toll‐Like Receptors (TLRs)‐Targeting Immunomodulatory Peptides |
| title_full_unstemmed | Massively Parallel Screening of Toll/Interleukin‐1 Receptor (TIR)‐Derived Peptides Reveals Multiple Toll‐Like Receptors (TLRs)‐Targeting Immunomodulatory Peptides |
| title_short | Massively Parallel Screening of Toll/Interleukin‐1 Receptor (TIR)‐Derived Peptides Reveals Multiple Toll‐Like Receptors (TLRs)‐Targeting Immunomodulatory Peptides |
| title_sort | massively parallel screening of toll interleukin 1 receptor tir derived peptides reveals multiple toll like receptors tlrs targeting immunomodulatory peptides |
| topic | age‐related macular degeneration peptides sepsis TIR domain Toll‐like receptors |
| url | https://doi.org/10.1002/advs.202406018 |
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