Targeting Toll-like receptor-driven systemic inflammation by engineering an innate structural fold into drugs
Abstract There is a clinical need for conceptually new treatments that target the excessive activation of inflammatory pathways during systemic infection. Thrombin-derived C-terminal peptides (TCPs) are endogenous anti-infective immunomodulators interfering with CD14-mediated TLR-dependent immune re...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-09-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-41702-y |
| _version_ | 1797558223074492416 |
|---|---|
| author | Ganna Petruk Manoj Puthia Firdaus Samsudin Jitka Petrlova Franziska Olm Margareta Mittendorfer Snejana Hyllén Dag Edström Ann-Charlotte Strömdahl Carl Diehl Simon Ekström Björn Walse Sven Kjellström Peter J. Bond Sandra Lindstedt Artur Schmidtchen |
| author_facet | Ganna Petruk Manoj Puthia Firdaus Samsudin Jitka Petrlova Franziska Olm Margareta Mittendorfer Snejana Hyllén Dag Edström Ann-Charlotte Strömdahl Carl Diehl Simon Ekström Björn Walse Sven Kjellström Peter J. Bond Sandra Lindstedt Artur Schmidtchen |
| author_sort | Ganna Petruk |
| collection | DOAJ |
| description | Abstract There is a clinical need for conceptually new treatments that target the excessive activation of inflammatory pathways during systemic infection. Thrombin-derived C-terminal peptides (TCPs) are endogenous anti-infective immunomodulators interfering with CD14-mediated TLR-dependent immune responses. Here we describe the development of a peptide-based compound for systemic use, sHVF18, expressing the evolutionarily conserved innate structural fold of natural TCPs. Using a combination of structure- and in silico-based design, nuclear magnetic resonance spectroscopy, biophysics, mass spectrometry, cellular, and in vivo studies, we here elucidate the structure, CD14 interactions, protease stability, transcriptome profiling, and therapeutic efficacy of sHVF18. The designed peptide displays a conformationally stabilized, protease resistant active innate fold and targets the LPS-binding groove of CD14. In vivo, it shows therapeutic efficacy in experimental models of endotoxin shock in mice and pigs and increases survival in mouse models of systemic polymicrobial infection. The results provide a drug class based on Nature´s own anti-infective principles. |
| first_indexed | 2024-03-10T17:28:17Z |
| format | Article |
| id | doaj.art-48831e2d95ee464f9b8c6ceb3f301034 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:28:17Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-48831e2d95ee464f9b8c6ceb3f3010342023-11-20T10:06:52ZengNature PortfolioNature Communications2041-17232023-09-0114112010.1038/s41467-023-41702-yTargeting Toll-like receptor-driven systemic inflammation by engineering an innate structural fold into drugsGanna Petruk0Manoj Puthia1Firdaus Samsudin2Jitka Petrlova3Franziska Olm4Margareta Mittendorfer5Snejana Hyllén6Dag Edström7Ann-Charlotte Strömdahl8Carl Diehl9Simon Ekström10Björn Walse11Sven Kjellström12Peter J. Bond13Sandra Lindstedt14Artur Schmidtchen15Division of Dermatology and Venereology, Department of Clinical Sciences, Lund UniversityDivision of Dermatology and Venereology, Department of Clinical Sciences, Lund UniversityBioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR)Division of Dermatology and Venereology, Department of Clinical Sciences, Lund UniversityDepartment of Clinical Sciences, Lund UniversityDepartment of Clinical Sciences, Lund UniversityDepartment of Clinical Sciences, Lund UniversityDepartment of Clinical Sciences, Lund UniversityDivision of Dermatology and Venereology, Department of Clinical Sciences, Lund UniversitySARomics Biostructures AB, Medicon VillageBioMS - Swedish National Infrastructure for Biological Mass SpectrometrySARomics Biostructures AB, Medicon VillageDivision of Mass Spectrometry, Department of Clinical Sciences, Lund UniversityBioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR)Department of Clinical Sciences, Lund UniversityDivision of Dermatology and Venereology, Department of Clinical Sciences, Lund UniversityAbstract There is a clinical need for conceptually new treatments that target the excessive activation of inflammatory pathways during systemic infection. Thrombin-derived C-terminal peptides (TCPs) are endogenous anti-infective immunomodulators interfering with CD14-mediated TLR-dependent immune responses. Here we describe the development of a peptide-based compound for systemic use, sHVF18, expressing the evolutionarily conserved innate structural fold of natural TCPs. Using a combination of structure- and in silico-based design, nuclear magnetic resonance spectroscopy, biophysics, mass spectrometry, cellular, and in vivo studies, we here elucidate the structure, CD14 interactions, protease stability, transcriptome profiling, and therapeutic efficacy of sHVF18. The designed peptide displays a conformationally stabilized, protease resistant active innate fold and targets the LPS-binding groove of CD14. In vivo, it shows therapeutic efficacy in experimental models of endotoxin shock in mice and pigs and increases survival in mouse models of systemic polymicrobial infection. The results provide a drug class based on Nature´s own anti-infective principles.https://doi.org/10.1038/s41467-023-41702-y |
| spellingShingle | Ganna Petruk Manoj Puthia Firdaus Samsudin Jitka Petrlova Franziska Olm Margareta Mittendorfer Snejana Hyllén Dag Edström Ann-Charlotte Strömdahl Carl Diehl Simon Ekström Björn Walse Sven Kjellström Peter J. Bond Sandra Lindstedt Artur Schmidtchen Targeting Toll-like receptor-driven systemic inflammation by engineering an innate structural fold into drugs Nature Communications |
| title | Targeting Toll-like receptor-driven systemic inflammation by engineering an innate structural fold into drugs |
| title_full | Targeting Toll-like receptor-driven systemic inflammation by engineering an innate structural fold into drugs |
| title_fullStr | Targeting Toll-like receptor-driven systemic inflammation by engineering an innate structural fold into drugs |
| title_full_unstemmed | Targeting Toll-like receptor-driven systemic inflammation by engineering an innate structural fold into drugs |
| title_short | Targeting Toll-like receptor-driven systemic inflammation by engineering an innate structural fold into drugs |
| title_sort | targeting toll like receptor driven systemic inflammation by engineering an innate structural fold into drugs |
| url | https://doi.org/10.1038/s41467-023-41702-y |
| work_keys_str_mv | AT gannapetruk targetingtolllikereceptordrivensystemicinflammationbyengineeringaninnatestructuralfoldintodrugs AT manojputhia targetingtolllikereceptordrivensystemicinflammationbyengineeringaninnatestructuralfoldintodrugs AT firdaussamsudin targetingtolllikereceptordrivensystemicinflammationbyengineeringaninnatestructuralfoldintodrugs AT jitkapetrlova targetingtolllikereceptordrivensystemicinflammationbyengineeringaninnatestructuralfoldintodrugs AT franziskaolm targetingtolllikereceptordrivensystemicinflammationbyengineeringaninnatestructuralfoldintodrugs AT margaretamittendorfer targetingtolllikereceptordrivensystemicinflammationbyengineeringaninnatestructuralfoldintodrugs AT snejanahyllen targetingtolllikereceptordrivensystemicinflammationbyengineeringaninnatestructuralfoldintodrugs AT dagedstrom targetingtolllikereceptordrivensystemicinflammationbyengineeringaninnatestructuralfoldintodrugs AT anncharlottestromdahl targetingtolllikereceptordrivensystemicinflammationbyengineeringaninnatestructuralfoldintodrugs AT carldiehl targetingtolllikereceptordrivensystemicinflammationbyengineeringaninnatestructuralfoldintodrugs AT simonekstrom targetingtolllikereceptordrivensystemicinflammationbyengineeringaninnatestructuralfoldintodrugs AT bjornwalse targetingtolllikereceptordrivensystemicinflammationbyengineeringaninnatestructuralfoldintodrugs AT svenkjellstrom targetingtolllikereceptordrivensystemicinflammationbyengineeringaninnatestructuralfoldintodrugs AT peterjbond targetingtolllikereceptordrivensystemicinflammationbyengineeringaninnatestructuralfoldintodrugs AT sandralindstedt targetingtolllikereceptordrivensystemicinflammationbyengineeringaninnatestructuralfoldintodrugs AT arturschmidtchen targetingtolllikereceptordrivensystemicinflammationbyengineeringaninnatestructuralfoldintodrugs |