NAVIGEN, INC. — Department of Health and Human Services SBIR Phase I: R

Description

DESCRIPTION provided by applicant Shiga toxins and Stx are the primary virulence factors of Shiga toxin producing E coli STEC which are major food and waterborne pathogens afflicting both developed and developing countries An estimated STEC infections occur annually in the US In addition to severe and often bloody diarrhea the life threatening complication hemolytic uremic syndrome HUS occurs in of victims primarily children No STEC vaccines or therapies beyond supportive care are available Antibiotics are not used since they can increase toxin production and risk of HUS The severity of STEC infection propensity for outbreaks and lack of effective treatments make STEC concerning potential bioterror agents and a public health priority Here we describe an innovative strategy to discover D peptide inhibitors of Stx to combat STEC infection D peptides the mirror images of natural L peptides cannot be digested by proteases and therefore have the potential for long in vivo half lives and low immunogenicity They can readily disrupt protein interfaces with high potency and specificity compared to small molecules and are much less expensive to produce than antibodies D peptides are ideal candidates for Stx neutralization in the gut and or systemic circulation Navigenandapos s drug discovery platform employs an enantiomeric screening technology mirror image phage display coupled with protein design We have successfully validated this platform technology by identifying D peptide inhibitors of HIV RSV and Ebola Our anti HIV D peptide was the first potent and specific D peptide inhibitor to be discovered and is in advanced preclinical trials It binds a functionally critical and conserved hydrophobic andquot pocketandquot on HIVandapos s trimeric surface glycoprotein gp A trimeric version of this D peptide binds to all three gp pockets providing a strong avidity boost Stx is each composed of a single enzymatically active A subunit and five receptor binding B subunits that form a pentameric ring Each of the B pentamer subunits contains a vulnerable pocket analogous to those of our viral targets The Stx B subunit pockets are excellent targets for us to next apply our expertise in D peptide drug design given our success in targeting analogous pockets at functionally critical interfaces the pentameric Stx target which inspires design of pentameric D peptides with strong avidity and the likelihood of D peptide stability and activity in the gut without disturbing native flora Furthermore the B subunits of Stx and Stx from Shigella dysenteriae are identical enabling dual therapeutic use for an anti Stx B D peptide These benefits have generated strong enthusiasm for this project from GI infectious disease clinicians who understand the dramatic potential impact an anti Stx D peptide would have in the clinic In this two year grant we propose to discover structurally characterize and optimize pentameric D peptide inhibitors that will neutralize Stx with high potency Success in this project will launch a new class of inhibitors against pathogenic bacteria important to global health PUBLIC HEALTH RELEVANCE Shiga toxin producing E coli STEC are dangerous pathogens that contaminate our food and water causing infections annually in the US Shiga toxins Stx and Stx Stx are the main virulence factors in STEC and can cause painful hemorrhagic colitis bloody diarrhea and life threatening hemolytic uremic syndrome HUS the leading cause of acute childhood renal failure Navigen is developing a novel protease stable Stx inhibitor since no STEC vaccines or treatments beyond supportive care are available