CAREER: Development of Chemical Tools for the Preparation of Strained Cyclic Peptides

Villanova University, Villanova PA

Investigators

Abstract

With the support of the Chemical Synthesis Program in the Division of Chemistry, Matthew O’Reilly of Villanova University is developing chemical tools for the preparation of strained cyclic peptides. Over 80 FDA approved peptide-based therapeutics exist, including insulin, which was the first drug of this class. While the synthesis and production of linear peptides, a straight chain of amino acids, is now seen as a relatively mature science, the use of linear peptides as therapeutics is limited by their general lack of bioavailability and in vivo stability. Often these limitations can be addressed if the peptide is cyclic, but cyclizing peptides via chemical synthesis remains challenging. Further, if the chain of amino acids is short enough, cyclization becomes even more challenging, as the final product has strain, and the molecular transitions leading to those products are geometrically less accessible. To address these challenges, the O’Reilly Lab is developing general tools to make strained cyclic peptides, unlocking them for the entire scientific community, where they can then be used in the areas of therapeutics, materials science, or catalysis. The synthetic methods are being validated through our synthesis of various biologically active strained cyclic peptide natural products. Beyond the purely scientific goals, this project will expand research opportunities at Villanova University to undergraduate researchers, and a course-based undergraduate research experience is being implemented in the undergraduate teaching curriculum to involve a broader audience in the research aims. Toward public engagement, collaboration with a children’s museum is planned to bring a facilitated exhibit focused on peptides to the public and to students. The research from the O’Reilly group is focused on developing consistent and reproducible methods that will be applied to the preparation of a wide variety of strained cyclic peptides. Initial efforts will be focused on the synthesis of cyclic tetrapeptides. The first objective involves the design and use of reagent arrays to facilitate cyclization, which will be simultaneously screened to examine reaction progress around a variety of parameters with rapid reaction analysis using liquid chromatography-mass spectrometry. As amino acid identity and stereochemistry have profound impacts on the rates of cyclization, computational efforts will be employed to evaluate product stability and the energetic considerations involved in cyclization. Combining the experimental data and computational insights are expected to provide for a more rational approach to the evaluation of strained cyclic peptides. The O'Reilly team will also examine auxiliary-mediated ligation approaches to facilitate cyclization to a less-strained, kinetic intermediate. The team anticipates that these intermediates will then undergo ring contraction to provide the strained, but thermodynamically favored amide products. If successful, these studies should provide improved access to cyclic peptides, especially ring strained variants for further exploration in 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.