The Future of Cysteine Cathepsins in Disease Management

组织蛋白酶 组织蛋白酶K 组织蛋白酶B 药物发现 炎症 药品 组织蛋白酶L 蛋白酵素 组织蛋白酶H 化学 半胱氨酸蛋白酶 组织蛋白酶C 疾病 组织蛋白酶D 医学 药理学 免疫学 生物化学 体外 破骨细胞
作者
Lovro Kramer,Dušan Turk,Boris Turk
出处
期刊:Trends in Pharmacological Sciences [Elsevier]
卷期号:38 (10): 873-898 被引量:134
标识
DOI:10.1016/j.tips.2017.06.003
摘要

The newly discovered roles of secreted cysteine cathepsins are dominating preclinical research, with major developments in pain regulation and cancer chemotherapy resistance. Cathepsin K inhibitors, including odanacatib, have all failed in osteoporosis clinical trials, but novel strategies to target cathepsin K are emerging. The antibody–drug conjugate field is dominated by cathepsin-cleavable linkers. First cathepsin-targeting imaging probes have entered clinical trials with favorable initial results. A new concept for targeted drug delivery based on cathepsin-targeting is emerging. Since the discovery of the key role of cathepsin K in bone resorption, cysteine cathepsins have been investigated by pharmaceutical companies as drug targets. The first clinical results from targeting cathepsins by activity-based probes and substrates are paving the way for the next generation of molecular diagnostic imaging, whereas the majority of antibody–drug conjugates currently in clinical trials depend on activation by cathepsins. Finally, cathepsins have emerged as suitable vehicles for targeted drug delivery. It is therefore timely to review the future of cathepsins in drug discovery. We focus here on inflammation-associated diseases because dysregulation of the immune system accompanied by elevated cathepsin activity is a common feature of these conditions. Since the discovery of the key role of cathepsin K in bone resorption, cysteine cathepsins have been investigated by pharmaceutical companies as drug targets. The first clinical results from targeting cathepsins by activity-based probes and substrates are paving the way for the next generation of molecular diagnostic imaging, whereas the majority of antibody–drug conjugates currently in clinical trials depend on activation by cathepsins. Finally, cathepsins have emerged as suitable vehicles for targeted drug delivery. It is therefore timely to review the future of cathepsins in drug discovery. We focus here on inflammation-associated diseases because dysregulation of the immune system accompanied by elevated cathepsin activity is a common feature of these conditions.
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