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Structural and Functional Analysis of the ApolipoproteinA-I A164S Variant
Department of Experimental Medical Science, Lund University, Lund, Sweden .
Department of Experimental Medical Science, Lund University, Lund, Sweden .
Department of Experimental Medical Science, Lund University, Lund, Sweden .
2015 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 11, p. e0143915-e0143915Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Public Library of Science (PLoS) , 2015. Vol. 10, no 11, p. e0143915-e0143915
National Category
Medical and Health Sciences Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:mau:diva-66852DOI: 10.1371/journal.pone.0143915ISI: 000365865300123PubMedID: 26605794Scopus ID: 2-s2.0-84955594337OAI: oai:DiVA.org:mau-66852DiVA, id: diva2:1853486
Available from: 2024-04-22 Created: 2024-04-22 Last updated: 2024-05-23Bibliographically approved

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