Peptide Stapling Using Conformationally Constrained Building Blocks

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With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Joshua Kritzer of Tufts University to develop new chemical building blocks that control the shape of peptides to mimic distinct conformations seen in proteins. Peptides are short polymer chains of amino acids that share many properties with larger proteins. The ability to control the three-dimensional shape or conformation of peptides allows the control of these properties and, consequently, their functions. In this project, chemical tethers are used to link an unnatural amino acid (one that is not found in terrestrial organisms) to another amino acid along the chain to constrain the shape of the peptide. The resulting peptides have potential applications in materials science, as catalysts and in drug development. In addition, the project prepares students to enter the science workforce through the development of a series of training workshops that help students practice professional skills, provide career guidance, and promote diversity and inclusion.The research project employs a new strategy for side-chain-mediated cross-linking, or “stapling,” that takes advantage of the unique conformational properties of the unnatural amino acid 4-mercaptoproline. Multiple independent strategies are used to incorporate 4-mercaptoproline staples into peptides, producing unique varieties of stapled beta-hairpins, stapled collagen-like helices and assemblies, and stapled bicyclic peptides. The three-dimensional structures of these designed structural scaffolds are determined by solution-state NMR spectroscopy. The effects of the new staples on biological degradation and cell penetration are examined through cell-based assays. The long term broader scientific impact of this work is to provide tools and methodology to control peptide architecture and biological stability and in so doing construct polypeptides with particular utility for studies 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.