High-Purity Peptide Libraries without Chromatographic Separation

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DESCRIPTION (provided by applicant): The market for peptide and protein products is $30 billion annually and continues to grow. Automated solid phase peptide synthesis (SPPS) is a mainstay of modern medicinal research, and has been used on micromole up to metric ton industrial scale. Peptide drugs such as Exenatide, a GLP-1 analogue and a life-saver to many type-2 diabetes patients, and Fuzeon for HIV-AIDS would not exist but for SPPS. Error sequences resulting from incomplete synthetic steps limit the efficiency and throughput of SPPS, often requiring laborious and costly separations. Our technology offers a novel solution to the problem via a chemical proofreading that takes place in the background (between standard condensation steps) with no modification to established methods. Within minutes, any unreacted sites are capped with inert fluorocarbon residues. The error sequences are thus reduced into insoluble constructs that can be removed in a facile manner at the end. Our preliminary studies have consistently afforded isolated full- length peptides, and especially in cases previously subject to repeated HPLC purification. We aim to expand this technology to the synthesis of error-free synthesis of peptide libraries. Achieving high purities would establish a new empowering standard in peptide research. Our research program at Tufts has experience in the study of G- Protein coupled receptors (GPCRs) and has produced notable innovations in the design and synthesis of novel peptide ligands. We therefore propose the synthesis of libraries of GLP-1 analogs, embodying novel and unnatural amino-acid motifs. Taken together, these studies will result in efficient library synthesis of peptides with purities exceeding 70% without the need for purification by chromatography and may result in a therapeutically relevant compound for diabetes at the end of the project period.