The objective of this proposal is the expansion of ribosomal translation to include ?-peptides as a means for the development of new protease inhibitors. Current therapeutics, split between small molecule drugs and biologics (such as monoclonal antibodies), leave many disease-relevant protein targets as being "undruggable." This deficiency presents an urgent need for new methods drug discovery. We propose the application of ribosomal translation using unnatural beta-amino acids to develop small molecules that mimic natural short peptides. These beta-amino acids can bestow valuable properties on peptides, improving their stability to degradation by proteases and, in some cases, targeting proteases as strong inhibitors. Because ribosome display technology allows high-throughput screening of translated peptides, the translation of beta-amino-acid-containing peptides provides a unique opportunity to develop and screen libraries of protease-inhibiting small molecules. To realize this goal, we will demonstrate and optimize the incorporation of beta-amino acids by the ribosome. We will then establish ribosome display for these beta-amino-acid-containing translation products, targeting the protein beta-secretase 1 (BACE1), the protease responsible for producing the amyloid-? proteins that aggregate in the brains of patients with Alzheimer's disease. In targeting BACE1-inhibitors with this ribosome display technology, we aim to identify new therapeutics while also establishing technology which can be applied generally in the screening of beta-amino acid containing peptidomimetics.
Current therapeutics leave many disease-relevant protein targets as being undruggable, presenting an urgent need for new methods for drug discovery. Developing the ribosomal translation of beta-amino acids offers the opportunity to create safe, stable, and active protease inhibitors as drug candidates. In targeting beta secretase 1-inhibitors with ribosome display technology, we will discover new therapeutics for Alzheimer's disease while also establishing technology which can be applied generally in the screening of beta-amino acid containing peptidomimetics.