Targeting Toll-like receptor-driven systemic inflammation by engineering an innate structural fold into drugs
(2023) In Nature Communications 14. p.1-20- 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... (More)
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.
(Less)
- author
- organization
-
- Dermatology and Venereology (Lund)
- Schmidtchen Lab (research group)
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- Thoracic Surgery
- Clinical and experimental lung transplantation (research group)
- Cardiothoracic anesthesia and intensive care (research group)
- BioMS (research group)
- WCMM-Wallenberg Centre for Molecular Medicine
- NPWT technology (research group)
- DCD transplantation of lungs (research group)
- LU Profile Area: Light and Materials
- publishing date
- 2023-09-29
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Animals, Mice, Swine, Lipopolysaccharides/metabolism, Toll-Like Receptors/metabolism, Inflammation/pathology, Peptides/chemistry, Peptide Hydrolases, Lipopolysaccharide Receptors/metabolism
- in
- Nature Communications
- volume
- 14
- article number
- 6097
- pages
- 1 - 20
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:37773180
- scopus:85172829154
- ISSN
- 2041-1723
- DOI
- 10.1038/s41467-023-41702-y
- language
- English
- LU publication?
- yes
- additional info
- © 2023. Springer Nature Limited.
- id
- a188849b-cfee-48ae-b97a-d94fca23593c
- date added to LUP
- 2023-10-05 10:49:45
- date last changed
- 2024-07-12 09:33:54
@article{a188849b-cfee-48ae-b97a-d94fca23593c, abstract = {{<p>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.</p>}}, author = {{Petruk, Ganna and Puthia, Manoj and Samsudin, Firdaus and Petrlova, Jitka and Olm, Franziska and Mittendorfer, Margareta and Hyllén, Snejana and Edström, Dag and Strömdahl, Ann-Charlotte and Diehl, Carl and Ekström, Simon and Walse, Björn and Kjellström, Sven and Bond, Peter J and Lindstedt, Sandra and Schmidtchen, Artur}}, issn = {{2041-1723}}, keywords = {{Animals; Mice; Swine; Lipopolysaccharides/metabolism; Toll-Like Receptors/metabolism; Inflammation/pathology; Peptides/chemistry; Peptide Hydrolases; Lipopolysaccharide Receptors/metabolism}}, language = {{eng}}, month = {{09}}, pages = {{1--20}}, publisher = {{Nature Publishing Group}}, series = {{Nature Communications}}, title = {{Targeting Toll-like receptor-driven systemic inflammation by engineering an innate structural fold into drugs}}, url = {{http://dx.doi.org/10.1038/s41467-023-41702-y}}, doi = {{10.1038/s41467-023-41702-y}}, volume = {{14}}, year = {{2023}}, }