Novel Chitohexaose Compounds to Treat Abdominal Peritonitis Leading to Sepsis

Abstract

Gastrointestinal perforation and appendicitis are the common cause of leakage of alimentary contents into the peritoneal cavity, leading to sepsis with a mortality rate between 14.7% and 29.9%. Besides its clinical challenge, the treatment of sepsis and its complications impose an enormous economic burden on health care systems worldwide. In sepsis caused by gram-negative bacteria, the bacterial endotoxin, lipopolysaccharide (LPS), activates the immune system through signaling the MD2-toll like receptor 4 complex (TLR4) to initiate the infection process for production of inflammatory cytokines (TNF-α, IL-1β, IL-6) that are responsible for hyperinflammation. Thus, development of antagonists that block these receptors either by inhibition of activation of TLRs or downstream signaling pathways would be beneficial in ameliorating the hyperinflammation if introduced early in the therapy. At AyuVis Research, we have designed a series of dual-acting small molecules (AVR-25, 48) that block TLR4 receptor, which inhibits the production of proinflammatory cytokines; stimulate production of macrophages leading to organ protection; and limit tissue injury. Our lead compound, AVR-25, has efficaciously demonstrated survival, organ protection, downregulation of inflammatory cytokines, and upregulation of M2 biomarkers and cytokines such as arginase-1 and IL-10 in vivo in a cecal ligation and puncture (CLP) sepsis mouse model via intravenous (IV) dosing. Our published and unpublished in silico modeling experiment has demonstrated that our compounds have a unique binding mode where they either bind to the dimerization site or to the middle of the TLR4 protein restricting the dimerization of protein, which is a critical step in downstream signaling. In our CLP model of both young and aged mice, compounds AVR-45 and AVR-48 efficaciously protected them against CLP-induced death and organ dysfunction at a 10-mg/kg (q8h) IV dose. These compounds also possess modest antibacterial activities against both gram-positive and gram-negative bacteria, as well as synergistic/additive activity in combination with standard of care antibiotics such as primaxin (PRM, Imipenem + cilastatin), indicating good potential for adjuvant antimicrobial therapy. We are the first and only key investigator team to observe the effects of AVR-25 and AVR-48 natural oligosaccharide-derived small molecules in preventing sepsis-induced death in the murine CLP-induced peritonitis model. We believe that development of this class of compounds will lead to a paradigm shift and could become a very high-gain project in the treatment management of inflammation and organ dysfunction in intra-abdominal sepsis. These significant research capabilities will open a new facet to combination therapy with antibiotic and standard antihypotensive agents for critically ill patients.