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

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

Nature Communications

10.1038/s41467-023-41702-y

http://dx.doi.org/10.1038/s41467-023-41702-y

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 Kjellstrom, Peter J. Bond, Sandra Lindstedt, Artur Schmidtchen

29 September 2023

Petruk, G., Puthia, M., Samsudin, F., Petrlova, J., Olm, F., Mittendorfer, M., Hyllén, S., Edström, D., Strömdahl, A.-C., Diehl, C., Ekström, S., Walse, B., Kjellström, S., Bond, P. J., Lindstedt, S., & Schmidtchen, A. (2023). Targeting Toll-like receptor-driven systemic inflammation by engineering an innate structural fold into drugs. Nature Communications, 14(1). https://doi.org/10.1038/s41467-023-41702-y

AbstractThere 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.

Attribution 4.0 International (CC BY 4.0)

This research / project is supported by the A*STAR - HTPO SEED ID
Grant Reference no. : C211418001

This research is supported by core funding from: Bioinformatics Institute (BII), A*STAR
Grant Reference no. : NA

This work was supported by grants from the Swedish Research Council (project 2017-02341, 2020-02016, 2021-06388), Edvard Welanders Stiftelse and Finsenstiftelsen (Hudfonden), the Royal Physiographic Society, the Crafoord, Österlund and Mats Paulsson Foundations, Vinnova and the Swedish Government Funds for Clinical Research (ALF).

https://oar.a-star.edu.sg/communities-collections/articles/20204

2041-1723

Bioinformatics Institute