New catalytic strategies to make non-proteinogenic peptides

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.

Grant Number: 5R35GM147169-04
NIH Institute/Center: NIH
Principal Investigator: Steven Bloom