Development of Nontoxic Peptides for Lipopolysaccharide Neutralization and Sepsis Treatment

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.