Anti-inflammatory effect of novel analogs of natural enkephalinase inhibitors in a mouse model of experimental colitis

Aim: The pharmacotherapy of inflammatory bowel disease is difficult and currently available treatments bring mostly poor and unsatisfactory results. Results: The purpose of this work was the synthesis of opiorphin, sialorphin, spinorphin and a series of their analogs and the in vitro characterization of their effect on degradation of enkephalin by neutral endopeptidase and aminopeptidase N. Consequently, we investigated in vivo the anti-inflammatory effect of the most active inhibitors selected in the in vitro studies (Pal-KKQRFSR & Pal-KKQHNPR). Putative inhibitor - enzyme (neutral endopeptidase or aminopeptidase N) complexes are also presented and their binding interfaces are identified. Conclusion: Our results suggest that Pal-KKQHNPR has the potential to become a valuable template for anti-inflammatory therapeutics for the treatment of GI tract inflammation.