α-Keto Amide Peptides: A Synthetic Strategy to Resin-Bound Peptide Isosteres for Protease Inhibitor Screening on Solid Support

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Abstract
A synthetic strategy for the formation of resin-bound internal α-keto amide peptides suitable for protease inhibitor screening on solid support is presented. This general approach is based on the incorporation of α-keto amide building blocks during solid-phase peptide synthesis (SPPS). Such dipeptidyl building blocks were accessible using the acylcyanophosphorane methodology. The acid-labile α-keto carbonyl functionality was protected as a 1,3-dithiolane derivative. This protective group is fully compatible with standard SPPS reaction conditions and can be efficiently removed with N-bromosuccinimide in 10% aqueous acetone. The α-keto amide peptides were assembled on SPOCC-1500 resin and were characterized with high-resolution magic angle spinning (HR-MAS) NMR on bead. The methodology was evaluated and tested with a variety of building blocks containing natural and nonnatural amino acid moieties.