Design and Synthesis of Dipeptide Nitriles as Reversible and Potent Cathepsin S Inhibitors

Citations Over Time

Abstract

The specificity of the immune response relies on processing of foreign proteins and presentation of antigenic peptides at the cell surface. Inhibition of antigen presentation, and the subsequent activation of T-cells, should, in theory, modulate the immune response. The cysteine protease Cathepsin S performs a fundamental step in antigen presentation and therefore represents an attractive target for inhibition. Herein, we report a series of potent and reversible Cathepsin S inhibitors based on dipeptide nitriles. These inhibitors show nanomolar inhibition of the target enzyme as well as cellular potency in a human B cell line. The first X-ray crystal structure of a reversible inhibitor cocrystallized with Cathepsin S is also reported.

Related Papers

• → Human Cathepsin V Functional Expression, Tissue Distribution, Electrostatic Surface Potential, Enzymatic Characterization, and Chromosomal Localization(1999)216 cited
• → Cysteine protease cathepsin S as a key step in antigen presentation(2004)29 cited
• → Human proteoglycan testican‐1 inhibits the lysosomal cysteine protease cathepsin L(2003)58 cited
• → Molecular Analysis and Enzymatic Characterization of Cathepsin B from Olive Flounder (Paralichthys olivaceus)(2014)4 cited
• → Crystal Structure of Human Cathepsin V,(2000)69 cited