Our laboratory is interested in topics at the interface of Chemistry and Biology, ranging from synthetic organic chemistry (in solution and on solid support), to exploring the folding, reactivity, and bioactivity of peptide mimics. We seek to develop innovative, broadly applicable tools for modifying and mimicking peptides that can be used to streamline peptide-based drug discovery efforts.
Progress in peptide mimicry requires the use and discovery of unnatural building blocks that (1) are able to maintain or expand the side-chain diversity of natural amino acids, (2) impart greater protease resistance, (3) adopt precise secondary structures, and (4) are easy to synthesize. We are particularly interested in unnatural amino acids that closely resemble the backbone of natural amino acids, such as aza-amino acids and N-substituted glycines (peptoids).
Information about our current projects can be found below:
1- Development of new chemoselective methods for the late-stage functionalization of peptides.
Our NSF-funded program in this area focuses mainly on the use of N-aryl peptides as novel tunable precursors for oxime and hydrazone peptide ligations reactions. Our discovery that Ca-substituted electron-rich N-aryl peptides can undergo oxidative coupling reactions under mild conditions (oxygen atmosphere, pH 7) has unlocked the potential of introducing a wide array of side chains at the site of ligation to give ketoxime/kethydrazone peptides. We are studying the conformational and structural properties of this class of underexplored peptide ligation products.
2-Expanding the toolbox of structure-inducing peptoid monomers.
We recently introduced the use of hydrazones as submonomers in solid phase peptoid synthesis, which provides access to diverse N-imino- and N-alkylamino glycine monomers with a wide array of (hetero)aryl and aliphatic side chains. Using X-ray crystallography, NMR spectroscopy, and computational analyses (in collaboration with Prof. Elon Ison), we have shown that these new monomers strongly favor the trans-amide bond geometry. The reduced N-alkylamino glycines possess a new hydrogen bond donor (NH) in the side chain, which is absent in most peptoid (N-substituted glycine) monomers. We are excited to continue expanding the use of these structure-inducing residues in peptide mimicry.
3-Expanding the chemistry and 'folding rules' of azapeptides.
We have contributed in two main areas related to azapeptides: 1) in the development of new methods to synthesize and functionalize azapeptides, including our recent report on the late-stage N-alkylation of azapeptides to access underexplored 'azapeptoids' and dialkylated azapeptides, and 2) in fundamental studies to quantify the impact of aza-amino acid on secondary structures such as beta-sheets. We look forward to continuing our efforts in both areas, with the aim to continue expanding the utility of azapeptides in medicinal chemistry applications.
Please contact Prof. Caroline Proulx for more information.