Development of Nontoxic Peptides for Lipopolysaccharide Neutralization and Sepsis Treatment.

Autor:	Fink A; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel.; MilliporeSigma Life Science, Kiryat Hamada 13, 9777613 Jerusalem, Israel., Ben Hur D; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel., Wani NA; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel., Cohen H; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel., Segev-Zarko LA; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel., Arnusch CJ; Department of Desalination and Water Treatment, Zuckerberg Institute for Water Research, Jacob Blaustein Institutes for Desert Research, Ben-Gurion University of the Negev, Sede-Boqer Campus 8499000, Israel., Shai Y; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel.
Jazyk:	angličtina
Zdroj:	ACS pharmacology & translational science [ACS Pharmacol Transl Sci] 2024 May 21; Vol. 7 (6), pp. 1795-1806. Date of Electronic Publication: 2024 May 21 (Print Publication: 2024).
DOI:	10.1021/acsptsci.4c00033
Abstrakt:	Host defense peptides (HDPs), also named antimicrobial peptides (AMPs), are increasingly being recognized for serving multiple functions in protecting the host from infection and disease. Previous studies have shown that various HDPs can also neutralize lipopolysaccharide (LPS, endotoxin), as well as lipoteichoic acid (LTA), inducing macrophage activation. However, antimicrobial activity is usually accompanied by systemic toxicity which makes it difficult to use HDPs as antiendotoxin agents. Here we report that key parameters can uncouple these two functions yielding nontoxic peptides with potent LPS and LTA neutralization activities in vitro and in animal models. The data reveal that peptide length, the number, and the placement of positive charges are important parameters involved in LPS neutralization. Crucially, the peptide exhibited a separation between its membrane-disrupting and antimicrobial properties, effectively decoupling them from its ability to neutralize LPS. This essential distinction prevented systemic toxicity and led to the peptide's complete rescue of mice suffering from severe septic shock in two distinct models. Strong binding to LPS, changes in structure, and oligomerization state upon LPS binding were important factors that determined the activity of the peptides. In the face of the increasing threat of septic shock worldwide, it is crucial to grasp how we can neutralize harmful substances like LPS. This knowledge is vital for creating nontoxic treatments for sepsis. Competing Interests: The authors declare no competing financial interest. (© 2024 American Chemical Society.)
Databáze:	MEDLINE
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