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

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 and Artur Schmidtchen
Additional contact information
Ganna Petruk: Lund University
Manoj Puthia: Lund University
Firdaus Samsudin: Technology and Research (A*STAR)
Jitka Petrlova: Lund University
Franziska Olm: Lund University
Margareta Mittendorfer: Lund University
Snejana Hyllén: Lund University
Dag Edström: Lund University
Ann-Charlotte Strömdahl: Lund University
Carl Diehl: SARomics Biostructures AB, Medicon Village
Simon Ekström: BioMS - Swedish National Infrastructure for Biological Mass Spectrometry
Björn Walse: SARomics Biostructures AB, Medicon Village
Sven Kjellström: Lund University
Peter J. Bond: Technology and Research (A*STAR)
Sandra Lindstedt: Lund University
Artur Schmidtchen: Lund University

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41702-y

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