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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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