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