Development of Specific and Potent α-Helical Inhibitors and Probes of Cysteine Proteases

Cysteine proteases are of great scientific and pharmaceutical interest due to their diverse roles in cellular processes and diseases. However, it has been difficult to design inhibitors for use in determining their individual roles due to the conserved active site. Interestingly, each protease has an endogenous inhibitor that forms an α-helix at the prime side of the active site. We developed a new method for stabilizing α-helices using natural amino acids that allowed us to make small peptides into α-helical inhibitors. We were then able to use structure based design to turn these α-helices into specific inhibitors and probes for use in understanding the proteases' roles in various diseases and cell processes. The use of α-helices has further implications as a new method of creating investigative tools for understanding proteases. new method of creating investigative tools for understanding proteases.