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Targeting Toll-like receptor-driven systemic inflammation by engineering an innate structural fold into drugs

Petruk, Ganna LU orcid ; Puthia, Manoj LU ; Samsudin, Firdaus ; Petrlova, Jitka LU ; Olm, Franziska LU orcid ; Mittendorfer, Margareta LU ; Hyllén, Snejana LU ; Edström, Dag LU ; Strömdahl, Ann-Charlotte LU and Diehl, Carl LU , et al. (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.

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organization
publishing date
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
  • scopus:85172829154
  • pmid:37773180
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
2024-04-19 01:59:19
@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}},
}