Oral/Topical D-peptide TNF Inhibitors for Inflammatory Bowel Disease

Project SummaryInflammatory bowel diseaseIBDaffects millions worldwideIBD can be divided into Crohn s DiseaseCDand Ulcerative ColitisUCboth of which are characterized by chronic inflammation in the gutleading to diarrheaulcerationbleedingand in many cases tumorsCurrentlymild to moderate IBD is treated orally with aminosalicylatesASAwhile more severe cases require the use of systemic immunosuppressants with serious side effectsAnti TNF biologics are effective for the treatment of moderate to severe IBDbut their high cost and immunosuppressive side effects limit their useespecially in childrenThe goal of this proposal is to develop a more targeted approacha non absorbable TNF inhibitor that can be delivered orally directly to sites of intestinal inflammationSpecificallywe propose to identify and optimize D peptide inhibitors of TNFD peptidesthe mirror images of natural L peptidescannot be digested by proteases andthereforethey survive transit through the gutFurthermorethey have the potential for long in vivo half livesand they have low immunogenicityThey can readily disrupt protein interfaces with high potency and specificity compared to small molecules and are much less expensive to produce than antibodiesNavigen and the Kay lab have extensive experience using an enantiomeric screening techniquemirrorimage phage displaycoupled with structure based design to develop highly potent and specific D peptide inhibitorse gviral entry inhibitors against HIVEbolaand respiratory syncytial virusOur anti HIV D peptide was the first potent and specific D peptide inhibitor to be discovered and is in advanced preclinical trialsSince D peptides are not absorbed from the gut and survive GI tract transitthey are ideal for the proposed oral topical inhibition of TNFin the gut mucosaInhibitory D peptides targeting TNFwould be idealbecausetheir resistance to proteolysis will enable oral topical deliverythey have minimal immunogenicitythey effectively block protein protein interactionsthey have a much lower cost of productionvsantibodiesandTNF s trimeric structure will allow us to make trimeric D peptide inhibitors with extreme affinity and potencytaking advantage of avidityIn thismonth SBIR grantwe will first identify D peptides that target our chemically synthesized D TNFThis will be followed by structural characterization and optimization to create a potent trimeric D peptide inhibitor of TNFwith which we will demonstrate activity in a mouse model of IBDOur primary goal is to develop a potent D peptide TNFinhibitor that will advance to more sophisticated animal models and INDenabling studies in Phase IIIn addition to providing a valuable and more cost effective option for IBD treatmentthis work will open the door to other localized applications for an anti TNFD peptideFinallysuccess in this project will greatly enable development of D peptides for other cellular targets PROJECT NARRATIVE Inflammatory bowel diseaseIBDis a serious chronic condition affecting millions worldwideCurrent biologic treatments targeting TNF a are effective for moderate to severe IBDbut they are immunogenicfrequently leading to loss of efficacyand cause systemic immune suppressionHerewe propose to develop a novel oral TNF inhibitorprotease resistant D peptidethat specifically inhibits TNF in the GI tracttreating IBD without losing efficacy over time or causing systemic side effects