Design of Protease Stable Therapeutic Peptides by Non-Perturbative Modification

PROJECT SUMMARY! Peptide therapeutics combine high potency and selectivityand engender fewer side effects than traditional small moleculesThis has fueled interest in peptides filling the gap between `biologicsandaposand small molecules as compounds that have key desired properties from both the other classesThere are however some challengesthe major one being susceptibility to enzyme catalyzed hydrolytic cleavage and inactivationWe propose here a strategy targeted towards an important class of peptide ligands that have therapeutic valueVia chemical modification using rapidhigh yielding reactions and through careful analysis of the key proteases involved in inactivationwe are able to generate large number of compounds that retain activities at their cognate receptor but are completely refractory to the frontline hydrolytic enzymesAt the end of Phase I studiescandidate peptides will be chosen to advance furtherBecause of the large number of derivatives possiblefine tuning of the pharmacological properties is achieved in a short period of timeOur technology also provides an easily adaptable platform to the broader community to stabilize their own peptide templates for preclinical development !PUBLIC HEALTH RELEVANCE STATEMENT The work proposed will create a platform technology to stabilize therapeutic peptides from being degraded by enzymesthus increasing their half lives in serumwhile maintaining biological activityThis should result in the improvement of potency and duration of effectfor an array of peptides that are suitable for treatment in a variety of disease conditions