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

• Published in: Nature communications 2023-09, Vol.14 (1), p.6097-6097, Article 6097
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 119/118; 13/21; 13/51; 140/131; 59/5; 631/154/309/2144; 631/250/256/1980; 64/110; 64/60; 82/16; 82/29; 82/58; Animal models; Animals; Antiinfectives and antibacterials; Basic Medicine; Biophysics; CD14 antigen; Cellular structure; Disseminated infection; Effectiveness; Endotoxin shock; Endotoxins; Farmaceutiska vetenskaper; Grooves; Humanities and Social Sciences; Immune response; Immune system; Immunomodulation; Immunomodulators; Immunosuppressive agents; In vivo methods and tests; Inflammation; Inflammation/pathology; Lipopolysaccharide Receptors/metabolism; Lipopolysaccharides/metabolism; Magnetic resonance spectroscopy; Mass spectrometry; Mass spectroscopy; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Mice; Molecular interactions; multidisciplinary; NMR; NMR spectroscopy; Nuclear magnetic resonance; Peptide Hydrolases; Peptides; Peptides/chemistry; Pharmaceutical Sciences; Protease; Proteins; Science; Science (multidisciplinary); Swine; Therapeutic targets; Thrombin; Toll-like receptors; Toll-Like Receptors/metabolism; Transcriptomes
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-41702-y

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. In this work, the authors report a drug class based on an ancient innate defense fold. Inspired by Nature’s anti-infective strategies, this peptide-based drug targets systemic inflammation via multiple molecular interactions, enhancing effectiveness