TY - JOUR
T1 - Targeting Toll-like receptor-driven systemic inflammation by engineering an innate structural fold into drugs
AU - Petruk, Ganna
AU - Puthia, Manoj
AU - Samsudin, Firdaus
AU - Petrlova, Jitka
AU - Olm, Franziska
AU - Mittendorfer, Margareta
AU - Hyllén, Snejana
AU - Edström, Dag
AU - Strömdahl, Ann-Charlotte
AU - Diehl, Carl
AU - Ekström, Simon
AU - Walse, Björn
AU - Kjellström, Sven
AU - Bond, Peter J
AU - Lindstedt, Sandra
AU - Schmidtchen, Artur
N1 - © 2023. Springer Nature Limited.
PY - 2023/9/29
Y1 - 2023/9/29
N2 - 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.
AB - 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.
KW - Animals
KW - Mice
KW - Swine
KW - Lipopolysaccharides/metabolism
KW - Toll-Like Receptors/metabolism
KW - Inflammation/pathology
KW - Peptides/chemistry
KW - Peptide Hydrolases
KW - Lipopolysaccharide Receptors/metabolism
UR - https://doi.org/10.1038/s41467-023-42294-3
U2 - 10.1038/s41467-023-41702-y
DO - 10.1038/s41467-023-41702-y
M3 - Article
C2 - 37773180
SN - 2041-1723
VL - 14
SP - 1
EP - 20
JO - Nature Communications
JF - Nature Communications
M1 - 6097
ER -