Sirtuin 激活剂和抑制剂：前景、成就与挑战。
Sirtuin activators and inhibitors: Promises, achievements, and challenges.
机构信息
GlaxoSmithKline, 1250S. Collegeville Road, Collegeville, PA 19426, USA.
Department of Genetics, Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, Boston, MA 02115, USA.
出版信息
Pharmacol Ther. 2018 Aug;188:140-154. doi: 10.1016/j.pharmthera.2018.03.004. Epub 2018 Mar 22.
Abstract
The NAD-dependent protein lysine deacylases of the Sirtuin family regulate various physiological functions, from energy metabolism to stress responses. The human Sirtuin isoforms, SIRT1-7, are considered attractive therapeutic targets for aging-related diseases, such as type 2 diabetes, inflammatory diseases and neurodegenerative disorders. We review the status of Sirtuin-targeted drug discovery and development. Potent and selective pharmacological Sirt1 activators and inhibitors are available, and initial clinical trials have been carried out. Several promising inhibitors and activators have also been described for other isoforms. Progress in understanding the mechanisms of Sirtuin modulation by such compounds provides a rational basis for further drug development.
摘要
Sirtuin 家族的 NAD 依赖性蛋白赖氨酸去酰基酶调节着从能量代谢到应激反应等各种生理功能。人类 Sirtuin 同工型 SIRT1-7 被认为是与衰老相关疾病（如 2 型糖尿病、炎症性疾病和神经退行性疾病）相关的有吸引力的治疗靶点。我们综述了 Sirtuin 靶向药物发现和开发的现状。目前已有有效的、选择性的药理学 Sirt1 激活剂和抑制剂，并且已经开展了初步的临床试验。其他同工型也有几种有前景的抑制剂和激活剂被描述。对这些化合物调节 Sirtuin 机制的理解的进展为进一步的药物开发提供了合理的基础。
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