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Targeting Toll-like...
Targeting Toll-like receptor-driven systemic inflammation by engineering an innate structural fold into drugs
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- Petruk, Ganna (författare)
- Lund University,Lunds universitet,Dermatologi och venereologi, Lund,Sektion III,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Dermatology and Venereology (Lund),Section III,Department of Clinical Sciences, Lund,Faculty of Medicine,Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, SE-22184, Lund, Sweden
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- Puthia, Manoj (författare)
- Lund University,Lunds universitet,Schmidtchen lab,Forskargrupper vid Lunds universitet,Schmidtchen Lab,Lund University Research Groups,Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, SE-22184, Lund, Sweden
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- Samsudin, Firdaus (författare)
- Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore, 138671, Singapore
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- Petrlova, Jitka (författare)
- Lund University,Lunds universitet,Schmidtchen lab,Forskargrupper vid Lunds universitet,Schmidtchen Lab,Lund University Research Groups,Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, SE-22184, Lund, Sweden
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- Olm, Franziska (författare)
- Lund University,Lunds universitet,Department of Clinical Sciences, Lund University, SE-22184, Lund, Sweden
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- Mittendorfer, Margareta (författare)
- Lund University,Lunds universitet,Thoraxkirurgi,Sektion II,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Thoracic Surgery,Section II,Department of Clinical Sciences, Lund,Faculty of Medicine,Department of Clinical Sciences, Lund University, SE-22184, Lund, Sweden
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- Hyllén, Snejana (författare)
- Lund University,Lunds universitet,Klinisk och experimentell lungtransplantation,Forskargrupper vid Lunds universitet,Thoraxanestesi och intensivvård,Clinical and experimental lung transplantation,Lund University Research Groups,Cardiothoracic anesthesia and intensive care,Department of Clinical Sciences, Lund University, SE-22184, Lund, Sweden; Department of Cardiothoracic Surgery, Anesthesia and Intensive Care, Skåne University Hospital, SE-22185, Lund, Sweden
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- Edström, Dag (författare)
- Lund University,Lunds universitet,Thoraxkirurgi,Sektion II,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Thoracic Surgery,Section II,Department of Clinical Sciences, Lund,Faculty of Medicine,Department of Clinical Sciences, Lund University, SE-22184, Lund, Sweden; Department of Cardiothoracic Surgery, Anesthesia and Intensive Care, Skåne University Hospital, SE-22185, Lund, Sweden
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- Strömdahl, Ann-Charlotte (författare)
- Lund University,Lunds universitet,Schmidtchen lab,Forskargrupper vid Lunds universitet,Schmidtchen Lab,Lund University Research Groups,Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, SE-22184, Lund, Sweden
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- Diehl, Carl (författare)
- SARomics Biostructures AB, Medicon Village, SE-22381, Lund, Sweden
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- Ekström, Simon (författare)
- Lund University,Lunds universitet,BioMS,Forskargrupper vid Lunds universitet,Lund University Research Groups,BioMS - Swedish National Infrastructure for Biological Mass Spectrometry, SE-22184, Lund, Sweden
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- Walse, Björn (författare)
- SARomics Biostructures AB, Medicon Village, SE-22381, Lund, Sweden
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- Kjellström, Sven (författare)
- Lund University,Lunds universitet,BioMS,Forskargrupper vid Lunds universitet,Lund University Research Groups,Division of Mass Spectrometry, Department of Clinical Sciences, Lund University, SE-22184, Lund, Sweden
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- Bond, Peter J (författare)
- Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore, 138671, Singapore; Department of Biological Sciences, National University of Singapore, Singapore, 117543, Singapore
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- Lindstedt, Sandra (författare)
- Lund University,Lunds universitet,DCD transplantation av lungor,Forskargrupper vid Lunds universitet,NPWT teknologin,Klinisk och experimentell lungtransplantation,WCMM- Wallenberg center för molekylär medicinsk forskning,Medicinska fakulteten,DCD transplantation of lungs,Lund University Research Groups,NPWT technology,Clinical and experimental lung transplantation,WCMM-Wallenberg Centre for Molecular Medicine,Faculty of Medicine,Department of Clinical Sciences, Lund University, SE-22184, Lund, Sweden; Department of Cardiothoracic Surgery, Anesthesia and Intensive Care, Skåne University Hospital, SE-22185, Lund, Sweden
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- Schmidtchen, Artur (författare)
- Lund University,Lunds universitet,Schmidtchen lab,Forskargrupper vid Lunds universitet,LU profilområde: Ljus och material,Lunds universitets profilområden,Schmidtchen Lab,Lund University Research Groups,LU Profile Area: Light and Materials,Lund University Profile areas,Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, SE-22184, Lund, Sweden; Dermatology, Skane University Hospital, SE-22185, Lund, Sweden
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(creator_code:org_t)
- Springer, 2023
- 2023
- Engelska.
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Ingår i: Nature Communications. - : Springer. - 2041-1723. ; 14, s. 1-20
- Relaterad länk:
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http://dx.doi.org/10... (free)
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https://doi.org/10.1...
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https://mau.diva-por... (primary) (Raw object)
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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https://urn.kb.se/re...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Nyckelord
- Animals
- Mice
- Swine
- Lipopolysaccharides/metabolism
- Toll-Like Receptors/metabolism
- Inflammation/pathology
- Peptides/chemistry
- Peptide Hydrolases
- Lipopolysaccharide Receptors/metabolism
Publikations- och innehållstyp
- art (ämneskategori)
- ref (ämneskategori)
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Petruk, Ganna
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Puthia, Manoj
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Samsudin, Firdau ...
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Petrlova, Jitka
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Olm, Franziska
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Mittendorfer, Ma ...
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visa fler...
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Hyllén, Snejana
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Edström, Dag
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Strömdahl, Ann-C ...
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Diehl, Carl
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Ekström, Simon
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Walse, Björn
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Kjellström, Sven
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Bond, Peter J
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Lindstedt, Sandr ...
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Schmidtchen, Art ...
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och Farmakologi och ...
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Nature Communica ...
- Av lärosätet
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Lunds universitet
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Malmö universitet