Thrombin-derived host defence peptide modulates neutrophil rolling and migration in vitro and functional response in vivo

Lim, Chun Hwee; Puthia, Manoj; Butrym, Marta; Tay, Hui Min; Lee, Michelle Zi Yi; Hou, Han Wei; Schmidtchen, Artur

doi:10.1038/s41598-017-11464-x

Cited by 8 publications

(7 citation statements)

References 54 publications

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“…This interference with TLR signaling provides a molecular explanation for the previously observed therapeutic effects of TCP-25 in experimental models of bacterial sepsis and endotoxin shock (27,32,33). In addition, the peptide reduces inflammatory responses to intact bacteria during phagocytosis (34) and inhibits neutrophil responses to LPS in vitro and in vivo (35).…”

Section: Introductionmentioning

confidence: 81%

A dual-action peptide-containing hydrogel targets wound infection and inflammation

et al. 2020

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There is a clinical need for improved wound treatments that prevent both infection and excessive inflammation. TCP-25, a thrombin-derived peptide, is antibacterial and scavenges pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide, thereby preventing CD14 interaction and Toll-like receptor dimerization, leading to reduced downstream immune activation. Here, we describe the development of a hydrogel formulation that was functionalized with TCP-25 to target bacteria and associated PAMP-induced inflammation. In vitro studies determined the polymer prerequisites for such TCP-25–mediated dual action, favoring the use of noncharged hydrophilic hydrogels, which enabled peptide conformational changes and LPS binding. The TCP-25–functionalized hydrogels killed Gram-positive Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa bacteria in vitro, as well as in experimental mouse models of subcutaneous infection. The TCP-25 hydrogel also mediated reduction of LPS-induced local inflammatory responses, as demonstrated by analysis of local cytokine production and in vivo bioimaging using nuclear factor κB (NF-κB) reporter mice. In porcine partial thickness wound models, TCP-25 prevented infection with S. aureus and reduced concentrations of proinflammatory cytokines. Proteolytic fragmentation of TCP-25 in vitro yielded a series of bioactive TCP fragments that were identical or similar to those present in wounds in vivo. Together, the results demonstrate the therapeutic potential of TCP-25 hydrogel, a wound treatment based on the body’s peptide defense, for prevention of both bacterial infection and the accompanying inflammation.

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Section: Introductionmentioning

confidence: 81%

A dual-action peptide-containing hydrogel targets wound infection and inflammation

et al. 2020

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“…Injury and infection are serious threats to the survival of an organism, and nature has therefore evolved powerful natural peptidebased mechanisms for controlling excessive bacterially-induced inflammation. Peptides derived from the C-terminus of thrombin (TCPs), initially discovered in human wounds 14 , control both bacterial infections and the associated inflammatory responses [15][16][17] via transient and multiple interactions with Gram-positive and negative-bacteria and their PAMPs, and subsequent interference with CD14-mediated TLR signaling [15][16][17] , neutrophil chemotaxis 18 , and excessive contact activation 17 .…”

mentioning

confidence: 99%

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

Petruk,

Puthia,

Samsudin

et al. 2023

Nat Commun

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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.

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“…Also thrombin released various active peptides (Papareddy et al 2010). It was indeed demonstrated that the thrombin derived hostdefense peptide GKY25 (GKYGFYTHVFRLKKWIQKVIDQFGE) deriving from the C-terminus of the protein inhibited LPS-induced responses of monocytes, macrophages, and neutrophils in vitro, ex vivo, and in vivo (Singh et al 2013;Hansen et al 2015;Lim et al 2017). GKY25 showed a broad and inhibitory effect on multiple sepsis pathologies.…”

Section: Miscellaneous Cryptidesmentioning

confidence: 99%

Cryptides: latent peptides everywhere

Iavarone

Desiderio

Vitali

et al. 2018

Critical Reviews in Biochemistry and Molecular Biology

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Proteomic surveys with top-down platforms are today revealing thousands of naturally occurring fragments of bigger proteins. Some of them have not functional meaning because they derive from pathways responsible for protein degradation, but many have specific functions, often completely different from that one of the parent proteins. These peptides encrypted in the protein sequence are nowadays called cryptides. They are frequent in the animal and plant kingdoms and represent a new interesting -omic field of investigation. To point out how much widespread is their presence, we describe here the most studied cryptides from very common sources such as serum albumin, immunoglobulins, hemoglobin, and from saliva and milk proteins. Given its vastness, it is unfeasible to cover the topic exhaustively, therefore only several selected examples of cryptides from other sources are thereafter reported. Demanding is the development of new -omic platforms for the functional screening of new cryptides, which could provide suggestion for peptides and peptido-mimetics with variegate fields of application.

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Thrombin-derived host defence peptide modulates neutrophil rolling and migration in vitro and functional response in vivo

Cited by 8 publications

References 54 publications

A dual-action peptide-containing hydrogel targets wound infection and inflammation

A dual-action peptide-containing hydrogel targets wound infection and inflammation

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

Cryptides: latent peptides everywhere

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