Project Grant R35GM155457

CHEMICAL METHODS TO PREPARE BIOACTIVE CYCLIC AND LASSOED PEPTIDE THERAPEUTICS - PROJECT SUMMARY THIS PROGRAM AIMS TO DEVELOP NEW CHEMICAL METHODS FOR THE PRACTICAL SYNTHESIS OF BIOACTIVE CYCLIC AND MICROCIN J25-INSPIRED LASSO PEPTIDE SCAFFOLDS. CYCLIC BIOACTIVE PEPTIDE NATURAL PRODUCTS WITH OXIDATIVE LINKAGES AT TYROSINE (TYR), AND OTHER PHENOLIC RESIDUES, HAVE INSPIRED OUR DEVELOPMENT OF RESIDUE-SELECTIVE STRATEGIES TO PREPARE TYR-LINKED (POLY)CYCLIC PEPTIDES. DEVELOPED PEPTIDE CYCLIZATION METHODS WILL IMMEDIATELY SUPPORT APPLICATIONS TOWARD CONSTRAINED ANTIMICROBIAL PEPTIDES. OVER THE NEXT FIVE YEARS, WE WILL DEVELOP STRATEGIES TO PREPARE CYCLIC/BICYCLIC PEPTIDES AND DEMONSTRATE THEIR POTENTIAL AS ANTIMICROBIAL PEPTIDE THERAPEUTIC LEADS. TARGETED APPLICATIONS WILL PREPARE STRUCTURE-STABILIZED ANTIMICROBIAL PEPTIDES WITH ANTICIPATED ACTIVITY AGAINST MULTIDRUG RESISTANT GRAM-NEGATIVE BACTERIA. THIS PROGRAM ALSO OUTLINES AN INTEGRATED EXPERIMENTAL AND COMPUTATIONAL PLATFORM TO ADDRESS THE STANDING CHALLENGE OF MICROCIN J25-INSPIRED LASSO PEPTIDE CHEMICAL SYNTHESIS. THIS INNOVATIVE APPROACH WILL DEVELOP METHODS TO ENABLE REVERSIBLE CYCLIZATION AND PROVIDE INFORMED FOLDING STABILIZATION CRITERIA TO ACCESS SYNTHETIC MICROCIN J25-INSPIRED LASSO PEPTIDES. WE WILL ITERATIVELY GUIDE THIS PROCESS WITH MOLECULAR DYNAMICS SIMULATIONS TO QUANTIFY LASSO FOLD STABILITY AND PROBABILITY. LONGER TERM, WE ANTICIPATE THAT DEVELOPED PEPTIDE CYCLIZATION AND LASSOING METHODS WILL ENABLE THE DESIGN AND SYNTHESIS OF NOVEL PEPTIDE THERAPEUTIC SCAFFOLDS TO ADDRESS CHALLENGING HUMAN DISEASE TARGETS.