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

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....

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Autores principales: Petruk, Ganna, Puthia, Manoj, Samsudin, Firdaus, Petrlova, Jitka, Olm, Franziska, Mittendorfer, Margareta, Hyllén, Snejana, Edström, Dag, Strömdahl, Ann-Charlotte, Diehl, Carl, Ekström, Simon, Walse, Björn, Kjellström, Sven, Bond, Peter J., Lindstedt, Sandra, Schmidtchen, Artur
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10541425/
https://www.ncbi.nlm.nih.gov/pubmed/37773180
http://dx.doi.org/10.1038/s41467-023-41702-y
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author Petruk, Ganna
Puthia, Manoj
Samsudin, Firdaus
Petrlova, Jitka
Olm, Franziska
Mittendorfer, Margareta
Hyllén, Snejana
Edström, Dag
Strömdahl, Ann-Charlotte
Diehl, Carl
Ekström, Simon
Walse, Björn
Kjellström, Sven
Bond, Peter J.
Lindstedt, Sandra
Schmidtchen, Artur
author_facet Petruk, Ganna
Puthia, Manoj
Samsudin, Firdaus
Petrlova, Jitka
Olm, Franziska
Mittendorfer, Margareta
Hyllén, Snejana
Edström, Dag
Strömdahl, Ann-Charlotte
Diehl, Carl
Ekström, Simon
Walse, Björn
Kjellström, Sven
Bond, Peter J.
Lindstedt, Sandra
Schmidtchen, Artur
author_sort Petruk, Ganna
collection PubMed
description 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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spelling pubmed-105414252023-10-01 Targeting Toll-like receptor-driven systemic inflammation by engineering an innate structural fold into drugs Petruk, Ganna Puthia, Manoj Samsudin, Firdaus Petrlova, Jitka Olm, Franziska Mittendorfer, Margareta Hyllén, Snejana Edström, Dag Strömdahl, Ann-Charlotte Diehl, Carl Ekström, Simon Walse, Björn Kjellström, Sven Bond, Peter J. Lindstedt, Sandra Schmidtchen, Artur Nat Commun Article 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. Nature Publishing Group UK 2023-09-29 /pmc/articles/PMC10541425/ /pubmed/37773180 http://dx.doi.org/10.1038/s41467-023-41702-y Text en © The Author(s) 2023, corrected publication 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Petruk, Ganna
Puthia, Manoj
Samsudin, Firdaus
Petrlova, Jitka
Olm, Franziska
Mittendorfer, Margareta
Hyllén, Snejana
Edström, Dag
Strömdahl, Ann-Charlotte
Diehl, Carl
Ekström, Simon
Walse, Björn
Kjellström, Sven
Bond, Peter J.
Lindstedt, Sandra
Schmidtchen, Artur
Targeting Toll-like receptor-driven systemic inflammation by engineering an innate structural fold into drugs
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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10541425/
https://www.ncbi.nlm.nih.gov/pubmed/37773180
http://dx.doi.org/10.1038/s41467-023-41702-y
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