Preclinical Study of a Novel LPS Inhibitor

Gram negative bacterial infections continue to account for significant mortality and morbiditydue the inability of new antibiotics to neutralize the deleterious effects of lipopolysaccharide (LPS)released from the bacterial cell surface. LPS initiates an immunoinflammatory cascade characterized byactivation of macrophages and other leukocytes, endothelial cells and parenchymal cells of liver, heart,etc. CAP18 is a novel protein that binds to and neutralizes LPS. CAP18 is comprised of two domains:a C-terminal 37 amino acid peptide fragment (designated RNIP-reactive nitrogen inhibitory peptide)inhibits LPS and interferon-gamma induced nitrogen radical production (IC50 = <50 Nm) and TNFrelease by macrophages and an N-terminal domain with cysteine proteinase inhibitor activity. The overallgoal of this work is to evaluate the therapeutic potential of the LPS binding peptide RNIP. This peptideis known to protect LPS-challenged mice and neutralize LPS generated cytokines in a whole blood assay.In Phase I, we will evaluate therapeutic efficacy of RNIP in two animal models of septic injury: guineapigs and swine. Phase II will be devoted to studies required for submission of an Investigational NewDrug Application including preclinical pharmacology and toxicology studies, development ofmanufacturing protocols (GMP), formulation work, and design of clinical trials. RNIP has therapeuticpotential for conditions associated with LPS-induced tissue injury and activation of mononuclearphagocytes such as sepsis, ARDS, burns, autoimmune diseases and AIDS.