PROJECT SUMMARY/ABSTRACT PEEL Therapeutics, Inc. (PEEL) is pioneering a novel approach to prevent morbidity and mortality associated with inflammatory disease through the inhibition of neutrophil extracellular traps (NETs). NETs are lattices of decondensed chromatin decorated with histones and antimicrobial proteins extruded by polymorphonuclear leukocytes (PMNs) to trap and kill microbes. While regulated NET formation contains infection, dysregulated NET formation leads to inflammatory tissue damage and vascular injury. NETs have been implicated in human diseases characterized by inflammation, including sepsis, stroke, diabetes, and heart disease. The ability of NET- inhibitory factors (NIFs) to block PMN-dependent NET formation makes this newly described class of endogenous peptides a promising therapeutic modality for diseases caused and/or exacerbated by NET-dependent inflammatory events. In this Phase I SBIR, PEEL will quantify and compare the biological activity and pharmacokinetics of two NIFs in vitro and in vivo. The lead NIF peptide will move forward in the development of a novel anti-NET therapeutic. After completing these SBIR Phase I tasks, PEEL Therapeutics will be in an excellent position to advance its new and patented NIF-based therapeutic to further preclinical studies. These efforts by PEEL Therapeutics hold the potential to disrupt and improve the treatment approach to both acute and chronic inflammatory diseases.