CHEMICAL STRATEGIES FOR CONFORMATIONAL CONTROL OF BIOACTIVE PEPTIDES

PROJECT SUMMARY To realize the potential of peptide- and protein-based therapeutics, conformational control is essential. Current strategies focus on either optimizing the amino-acid sequence toward a desired structure or creating covalent bonds between amino-acid side chains to restrict conformational flexibility. Though these strategies have demonstrated important successes, they require extensive optimization and limit the availability of side-chain functionalities that could instead be optimized for target engagement. A central goal of our laboratory is therefore to develop more general strategies to specify peptide/protein structure. To do so, we will evaluate new chemical approaches to preorganize individual amino acids without sacrificing side-chain functionality. Inspired by differences in the conformational propensities of natural amino acids, we will synthesize minimally modified amino-acid analogs that favor specific secondary structures. Initial priorities include the synthesis of amino-acid analogs that modify their proteinogenic counterparts’ intrinsic propensities to adopt beta-sheet secondary structures. We are also interested in controlling the conformation and interactions of glycine residues, which play a unique role in protein structure and yet remain difficult to constrain. After synthesizing a suite of novel amino-acid analogs, we will evaluate their conformational propensities by studying the folding thermodynamics of model peptides/proteins that incorporate these residues. We will also evaluate the ability of peptides incorporating modified amino acids to engage with important biological targets, especially misfolded proteins and transmembrane helices. Our results will inform the design of peptides and proteins with improved conformational control, thereby supporting a variety of applications across medicine and biotechnology.