CAREER: Synthesis of Functional Biomolecules from Tunable N-aryl Peptide Precursors

With the support of the SYN program in the Division of Chemistry, Dr. Caroline Proulx of North Carolina State University (NCSU) will pursue fundamental research in bioorganic chemistry, with a focus on developing new methods for the synthesis of peptide- and protein-mimicking libraries. Peptides play vital roles in modulating biological function.

Their ability to bind to their targets with high affinity and selectivity is dependent on both their chemical composition and conformation. As such, tools to rapidly modify and control both are required to streamline drug discovery efforts. In this project, novel methods are developed to achieve these goals.

Selective chemical transformations are developed for late-stage peptide functionalization, and methods are developed for their subsequent cyclization/ligation under mild aqueous conditions. Strategic incorporation of functional groups is explored to control the conformation and stability of the resulting peptide or protein mimics. Broader impacts of the project will include continued mentoring and training of ACS Project SEED high school students and NSF REU students during the summer, as well as educational presentations in high schools across North Carolina.

Virtual lab tours and other videos will also be produced in collaboration with the Science House at NCSU.

Under this award, Dr. Caroline Proulx will develop new methods to access conformationally-constrained, highly functionalized ketoxime and kethydrazone peptides starting from tunable N-aryl peptide precursors. These substrates are expected to undergo triggered ligations under catalyst-free aqueous conditions that also exhibit high functional group tolerance.

This project aims to introduce a wide array of side chain chemistry at the site of ligation using late-stage peptide functionalization reactions. The alpha-carbon substituent will be used to better mimic natural amino acid side chains, fine-tune stability of the linkage, and control E/Z ratios in the resulting kethydrazone or ketoxime-linked peptides.

In addition, the N-aryl ring will be tuned to enable one-pot, sequential ligation for the synthesis of protein-length material. In the longer term, this work seeks to lay the groundwork for the establishment of structure-folding-function rules for this new class of unnatural peptide- and protein-mimicking oligomers for chemical biology.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.