8BWW

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

Summary for 8BWW

• Entry DOI: 10.2210/pdb8bww/pdb
• NMR Information: BMRB: 34778
• Descriptor: Thrombin light chain (1 entity in total)
• Functional Keywords: host defence peptide, cd14, bacterial lps, de novo protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 2287.85

Authors

Diehl, C. (deposition date: 2022-12-07, release date: 2023-09-06, Last modification date: 2024-11-20)

Primary citation

Petruk, G.,Puthia, M.,Samsudin, F.,Petrlova, J.,Olm, F.,Mittendorfer, M.,Hyllen, S.,Edstrom, D.,Stromdahl, A.C.,Diehl, C.,Ekstrom, S.,Walse, B.,Kjellstrom, S.,Bond, P.J.,Lindstedt, S.,Schmidtchen, A.
Targeting Toll-like receptor-driven systemic inflammation by engineering an innate structural fold into drugs.
Nat Commun, 14:6097-6097, 2023

PubMed 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.

PubMed: 37773180
DOI: 10.1038/s41467-023-41702-y

Experimental method

SOLUTION NMR