Peptide mimetics is an attractive method to identify potential binding partners for otherwise difficult targets. Peptides are easier to manipulate and optimize over larger more traditional pharmaceutical compounds. Peptidic scaffolds are structured peptides that have serve as a backbone for functional groups to be grafted upon. The objective of the project is to produce peptides with a library of reversibly exchangeable functional groups for applications in drug discovery. The group utilizes dynamic combinatorial chemistry (DCC) to create a library of building blocks. When the library is introduced to a target, the library progresses to the target-building block configuration that is the most stable while leaving the rest of the building blocks in solution according to Le Chatelier’s Principle. The group uses cysteines to produce disulfide bonds between the peptide scaffold and the building blocks. For these studies to be successful, information about the scaffolds and every single building block to be included in the library must be collected. Peptide scaffolds were synthesized with solid phase peptide synthesis using a Fmoc strategy with chlorotrityl resin beads, then cyclized. Multiple DCC experiments were performed with varying levels of complex libraries, composed of scaffolds and building blocks. High performance liquid chromatography (HPLC), Matrix Assisted Laser Desorption/Ionization Time-of-Flight (MALDI TOF) mass spectrometry, and Nuclear Magnetic Resonance spectroscopy (NMR) were utilized to verify the purity and identity of peptide scaffolds. Progress of these reactions were analyzed using HPLC and characterized by MALDI TOF. Optimization of peptide scaffold structure and building block libraries are still underway.

Design of protein mimetics by dynamic combinatorial chemistry on folded peptidic scaffolds

2019 Spring National Meeting

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