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

2002; American Chemical Society; Volume: 45; Issue: 25 Linguagem: Inglês

10.1021/jm020209i

1520-4804

Yancey D. Ward, David Thomson, Leah L. Frye, Charles L. Cywin, Tina M. Morwick, Michel J. Emmanuel, Renée Zindell, Daniel W. McNeil, Younes Bekkali, Marc Girardot, Matt Hrapchak, Molly DeTuri, K. Crane, Della White, Susan Pav, Yong Wang, Ming‐Hong Hao, Christine A. Grygon, Mark E. Labadia, Dorothy M. Freeman, Walter Davidson, Jerry L. Hopkins, Maryanne L. Brown, Denice M. Spero,

Antimicrobial Peptides and Activities

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.