Targeting endogenous sialidases for treatment of endotoxic shock

DESCRIPTION provided by applicant Despite the advance of antibiotics sepsis remains a major challenge to human health as both survival and incidence of severe sepsis have been largely unchanged in the last two decades It is therefore important to develop new therapeutic approaches We have recently reported that bacterial sialidases may serve as therapeutic targets for polybacterial sepsis However since the majority of bacteria that cause sepsis do not encode sialidases targeting bacterial sialidases alone would be insufficient for therapy of sepsis In order to expand the original concept to infections by microbes that do not produce sialidases we hereby hypothesize that host sialidases can also be targeted for the treatment of sepsis In support of this notion we observed that a novel sialidase inhibitor deoxy dehydro N glycolylneuraminic acid Neu Gc en conferred protection against lethal endotoxic shock Since endotoxin does not contain microbial sialidases the inhibitor has to target the host sialidase s Furthermore using mice with a targeted mutation of Neu gene among the hematopoietic cells we demonstrated a critical role for NEU in both severity of endotoxic shock and in therapeutic response to Neu Gc en These results demonstrate that NEU is a potential therapeutic target for endotoxic shock which contributes to pathogenesis of sepsis and remains largely unresponsive to current therapy Based on these exciting observations we will compare therapeutic effect of a series of newly synthesized sialidase inhibitors for their activity and selectivity for NEU The goal is to identify a lead compound tha is effective in treating endotoxic shock with minimal toxicity PUBLIC HEALTH RELEVANCE Despite availability of antibiotics the mortality and hospitalization of severe sepsis increased rapidly between and causing approximately annual deaths in US alone A major proportion of septic shock was caused by endotoxin LPS producing Gram negative bacteria Our proposed studies may provide a novel therapeutic approach for septic shock