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Stapling a host defense peptide for boosted dual targeting of CD14 and bacterial LPS

ABSTRACT: Excessive Toll like receptor (TLR) and NF-kB activation during infection causes the overactivation of inflammatory pathways seen in sepsis. Thrombin-derived C-terminal peptides (TCP) target both bacteria and the resulting TLR-mediated inflammatory response during infection. The present study describes the design and development of a novel multifunctional stapled peptide mimicking the actions of such immunomodulatory TCPs, providing a new drug class based on natures own anti-infective strategies. Using a combination of structure-based design, nuclear magnetic resonance spectroscopy (NMR), biophysical, mass spectrometry, microbiological, cellular, and in vivo studies, we describe the development of a structurally locked active stapled form of the endogenous peptide HVFRLKKWIQKVIDQFGE, denoted sHVF18. The stapled peptide shows a higher affinity to CD14 than the linear peptide, retains a partly helical and stabilized structure, and is protease resistant. In vivo, it shows efficacy in experimental models of endotoxin shock in mice and pigs and increases survival in mouse models of polymicrobial sepsis.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Artur Schmidtchen

PROVIDER: MSV000090815 | MassIVE | Wed Nov 30 03:43:00 GMT 2022

REPOSITORIES: MassIVE

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Effect of LPS, sHVF18 and the combination therof on gene expression in murine lungs

Project description:Excessive Toll-like receptor (TLR) and NF-kB activation during infection causes the overactivation of inflammatory pathways seen in sepsis. Thrombin-derived C-terminal peptides (TCPs) target both bacteria and the resulting TLR-mediated inflammatory response during infection. The present study describes the design and development of a novel multifunctional stapled peptide mimicking the actions of such immunomodulatory TCPs, providing a new drug class based on nature’s own anti-infective strategies. Using a combination of structure-based design, nuclear magnetic resonance spectroscopy (NMR), biophysics, mass spectrometry, microbiology, cellular, and in vivo studies, we describe the development of a structurally locked active stapled form of the endogenous peptide HVFRLKKWIQKVIDQFGE, denoted sHVF18. The stapled peptide shows a higher affinity to CD14 than the linear peptide, retains a partly helical and stabilized structure, and is protease resistant. In vivo, it shows efficacy in experimental models of endotoxin shock in mice and pigs and increases survival in mouse models of polymicrobial sepsis.

2024-01-01 | GSE217695 | GEO

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2011-10-14 | E-MEXP-2944 | biostudies-arrayexpress

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2014-02-21 | E-GEOD-55238 | biostudies-arrayexpress

Transcription profiling of human lymphocyte response to E. coli to identify any transcriptional component to the protection in vitro bacterially induced PBMC apoptosis

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2023-06-12 | GSE221652 | GEO

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Project description:Sepsis is a complex syndrome associated with physiological, pathological, and biochemical abnormalities resulting from infection. Sepsis is the major cause of acute respiratory distress syndrome (ARDS). Extracellular vesicles (EVs) are serving as new messengers to mediate cell-cell communication in vivo. The function of EVs in sepsis patients are not well defined. We found sepsis EV encapsulating G6PD induced pro-inflammatory effects in the lung tissue by reprogramming purine metabolism. Most notably, guanine accumulation led to EZH2-mediated H3K27Me3 level. Finally Our study provides a novel mechanism of how EV reviried puring metabolism in lung tissue and leading to acute lung damage.

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