Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY/ABSTRACT G protein-coupled receptors (GPCRs) are venerable targets for drug discovery. One-third of all drugs in clinical use target a GPCR. The endogenous ligands for many GPCRs are peptides, which make peptides ideal probes for exploring the structure-activity relationship of these GPCRs, and for developing drugs that modulate their activity. While a select few native GPCR peptide ligands have been successfully translated into human therapies, the vast majority are plagued by inadequate PK/PD properties and make very poor drugs. Replacing the natural amino acids (AAs) in the peptide with non-proteinogenic amino acids (NPAAs) can enhance the drug- like properties of ordinary peptides, thereby improving their practical use as medicines. 80% of all GPCR peptide drugs contain NPAAs. Determining which NPAAs to include in the peptide and where to place them largely depends on trial and error, each peptide variant being made as the unique product of a separate multi-step solid- phase chemical synthesis procedure that relies on a limited pool of NPAAs with poor solid-phase coupling efficiencies. New technologies which enable NPAAs to be introduced into peptides in a general, synthetically divergent, and cost-effective manner would (1) considerably improve GPCR peptide drug development as it is practiced today, (2) enable access to comprehensive peptide libraries to thoroughly explore structure-activity relationships of GPCRs, and (3) promote the development and deployment of new synthetic methods, which will in turn advance the fields of synthetic chemistry and medicinal peptide chemistry. Our laboratory has developed a new parallel synthesis approach that generates entire libraries of individual peptide analogs in a single step. We have shown that this strategy can yield libraries of peptides wherein a single amino acid is transformed to one of a myriad of new NPAA variants. To further develop our strategy as a general tool for medicinal chemistry and demonstrate its advantages for optimizing GPCR peptides we propose here to generate and to evaluate libraries of a new GPCR peptide ligand designed by our lab that has promising anti-HIV activity. By pursuing both chemistry and biology in parallel we will use our new peptide as a vehicle to refine and improve our newly minted chemical methodology to prepare (1) peptides with multiple NPAAs, and (2) peptides containing D-amino acids, which will advance our peptide as an entirely new antiretroviral drug and will make our synthetic platform more useful for GPCR peptide drug development.
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