Chapter 5:Targeting Dipeptidyl Peptidase-4 (DPP-4) and Fibroblast Activation Protein (FAP) for Diabetes and Cancer Therapy
Chapter 5:Targeting Dipeptidyl Peptidase-4 (DPP-4) and Fibroblast Activation Protein (FAP) for Diabetes and Cancer Therapy
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第 5 章：靶向二肽基肽酶 4 (DPP-4) 和成纤维细胞激活蛋白 (FAP) 治疗糖尿病和癌症
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发表时间：
2011
期刊：
影响因子：
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通讯作者：
Denise M. T. Yu
中科院分区：
文献类型：
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作者：
F. Keane;S. Chowdhury;Tsun‐Wen Yao;N. A. Nadvi;Margaret G. Gall;Yiqian Chen;B. Osborne;A. J. Ribeiro;W. B. Church;G. McCaughan;M. Gorrell;Denise M. T. Yu
近年来，二肽基肽酶-4（DPP-4）酶家族引起了强烈的药学兴趣。DPP-4抑制剂已被证明是治疗日益增长的2型糖尿病流行病的成功疗法，并有可能治疗其他疾病。大量最近开发的DPP-4抑制剂处于临床开发的各个阶段，其中四种谷胱甘肽类抑制剂已在临床使用。成纤维细胞活化蛋白（FAP）是DPP-4的近亲，其独特的分布导致了对其作为上皮癌的靶点和标志物的大量研究。新成员DPP-8和DPP-9的作用尚未完全确定，但早期证据表明可能在细胞生物学和疾病的各个方面发挥作用。有许多有利的情况有助于靶向DPP-4和FAP的治疗方法。DPP-4和FAP的特异性靶向更容易通过该酶家族的小尺寸和其活性位点的几个结构差异来实现。此外，在过去十年中观察到DPP-4和FAP基因敲除小鼠是健康的，这表明选择性抑制这些蛋白酶中的每一种都是安全的，这反映在DPP-4选择性格列汀的优异安全性特征中。这些蛋白质还具有预期在蛋白酶抑制剂存在下保留的有趣的酶外活性。这一特点也表明脱靶效应的可能性很低。因此，对DPP-4和FAP结构-功能关系、分布以及酶和酶外生物学作用的全面了解提供了对它们作为疾病靶点的治疗有用性的深入了解。
In recent years, the dipeptidyl peptidase-4 (DPP-4) enzyme family has created intense pharmaceutical interest. DPP-4 inhibitors have proven successful as a therapy for the growing type 2 diabetes epidemic and have potential to treat other diseases. A large number of recently developed DPP-4 inhibitors are in various phases of clinical development, with four gliptin class inhibitors already in clinical use. The unique distribution of Fibroblast Activation Protein (FAP), the closest relative of DPP-4, has led to numerous investigations of it as a target and marker for epithelial cancers. The roles of the newer members, DPP-8 and DPP-9, are yet to be fully characterized, but early evidence suggests possible roles in various aspects of cell biology and disease. There are a number of favorable circumstances that have contributed to the therapeutic approaches of targeting DPP-4 and FAP. Specific targeting of DPP-4 and FAP is made easier by the small size of this enzyme family and several structural differences at their active sites. Additionally, observations over the past decade that the DPP-4 and FAP gene knockout mice are healthy suggests that selective inhibition of each of these proteases would be safe, and this is reflected in the excellent safety profiles of the DPP-4-selective gliptins. These proteins also have interesting extra-enzymatic activities that are expected to be retained in the presence of protease inhibition. This feature also points to a low likelihood of off-target effects. Thus, an overall understanding of DPP-4 and FAP structure–function relationships, distribution, and enzymatic and extra-enzymatic biological roles provides an insight into their therapeutic usefulness as disease targets.