Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 MerryfieldRow, San Diego, CA 92121, USA.
Curr Top Med Chem. 2010;10(7):717-32. doi: 10.2174/156802610791113432.
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.
组织蛋白酶 S 作为一种医学化学靶点，其重要性日益增加，因为它在调节主要组织相容性复合体 II（MHC II）分子的抗原呈递中发挥作用，并且参与细胞外蛋白水解活性。组织蛋白酶 S 酶的抑制作用可减少不变链的降解，不变链是一种关键的伴侣分子，也可阻止 MHC II 分子与肽结合，从而减少 CD4(+)T 细胞的抗原呈递。细胞外组织蛋白酶 S 还可能通过裂解膜结合趋化因子 fractalkine（CX3CL1）参与血管生成以及神经病理性疼痛的起始和/或维持。因此，组织蛋白酶 S 抑制剂被认为具有治疗多种疾病的潜力。组织蛋白酶 S 抑制剂的最初开发靶向的是不可逆的、共价抑制剂，但最近的重点是可逆抑制剂，包括酶的共价修饰物，以及最近的非共价抑制剂。本文综述了自 2006 年以来在主要文献中报道的组织蛋白酶 S 抑制剂设计的进展，特别关注了各种共价和非共价抑制剂系列的结构活性关系。
