Recent Advances in the Design of Cathepsin S Inhibitors

Title: Recent Advances in the Design of Cathepsin S Inhibitors

Volume: 10 Issue: 7

Author(s): John J. M. Wiener, Siquan Sun and Robin L. Thurmond

Affiliation:

Keywords: Cathepsin S, inhibitor, antigen presentation, protease, autoimmune disease, inflammation, immunomodulator, covalent binding, noncovalent binding

Abstract: Cathepsin S has been of increasing interest as a target of medicinal chemistry efforts given its role in modulating antigen-presentation by major histocompatibility class II (MHC II) molecules as well as its involvement in extracellular proteolytic activities. Inhibition of the cathepsin S enzyme reduces degradation of the invariant chain, a crucial chaperon which also blocks peptide-binding by MHC II molecules, thereby decreasing antigen presentation to CD4+ T-cells. Extracellular cathepsin S may also be involved in angiogenesis and initiation and/or maintenance of neuropathic pain by cleavage of the membrane-bound chemokine fractalkine (CX3CL1). Cathepsin S inhibitors have thus been suggested to hold potential as therapeutics for a variety of diseases. The initial development of cathepsin S inhibitors targeted irreversible, covalent inhibitors, but more recently the focus has been on reversible inhibitors, representing both covalent modifiers of the enzyme and, of late, noncovalent inhibitors. This review details advances in cathepsin S inhibitor design as reported in the primary literature since 2006, focusing especially on structure-activity relationships of the various covalent and noncovalent inhibitor series.

Cite this article as:

J. M. Wiener John, Sun Siquan and L. Thurmond Robin, Recent Advances in the Design of Cathepsin S Inhibitors, Current Topics in Medicinal Chemistry 2010; 10 (7) . https://dx.doi.org/10.2174/156802610791113432