Molecular and Cellular Pharmacology, Discovery Sciences, Janssen R&D, San Diego, CA 92121, United States.
Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY 10032, United States; Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, United States.
Biochem Pharmacol. 2017 Jul 1;135:1-11. doi: 10.1016/j.bcp.2017.02.010. Epub 2017 Feb 16.
Maintaining the integrity of cellular membranes is critical to protecting metabolic activities and genetic information from the environment. Regulation of transport across membranes of essential chemicals, including water, nutrients, hormones and many drugs, is therefore key to cellular homeostasis and physiological processes. The two main transporter superfamilies are ATP-binding cassette (ABC) transporters that primarily function as efflux transporters, and the solute carrier (SLC) transporters. SLC transporters encompass 52 gene families with almost 400 different human transporter genes. Although long under-explored, SLC transporters are an emerging drug target class and the molecular target of several approved inhibitor drugs, such as selective serotonin reuptake inhibitors (SSRIs) for depression and sodium/glucose co-transporter (SGLT2) inhibitors for diabetes. Interestingly though, although loss-of-function mutations in numerous human SLC transporters are linked to Mendelian diseases, few reports of SLC transporter activators have appeared, and only inhibitors have been advanced to clinical studies. In this commentary, we discuss several strategies for potentiating SLC transporter function, from direct acting potentiators to modulators of transcription, translation or trafficking. We review the progress made in recent years toward the understanding of the structural and molecular basis of SLC transporter function and the pathways and mechanisms that regulate SLC expression, and describe the opportunities these new insights present for discovery of SLC transporter potentiators. Finally, we highlight the challenges associated with the various approaches and provide some thoughts on future directions that might facilitate the search for SLC potentiators with therapeutic potential.
维持细胞膜的完整性对于保护代谢活动和遗传信息免受环境影响至关重要。因此，调节包括水、营养物质、激素和许多药物在内的重要化学物质跨膜的运输，是细胞内稳态和生理过程的关键。两个主要的转运体超家族是 ATP 结合盒（ABC）转运体，主要作为外排转运体发挥作用，以及溶质载体（SLC）转运体。SLC 转运体包含 52 个基因家族，有近 400 种不同的人类转运体基因。尽管长期以来研究不足，但 SLC 转运体是一个新兴的药物靶点类别，也是几种已批准的抑制剂药物的分子靶点，如用于治疗抑郁症的选择性 5-羟色胺再摄取抑制剂（SSRIs）和用于治疗糖尿病的钠/葡萄糖协同转运蛋白（SGLT2）抑制剂。然而，有趣的是，尽管许多人类 SLC 转运体的功能丧失突变与孟德尔疾病有关，但很少有关于 SLC 转运体激活剂的报道，只有抑制剂被推进到临床研究中。在这篇评论中，我们讨论了几种增强 SLC 转运体功能的策略，从直接作用的增强剂到转录、翻译或运输的调节剂。我们回顾了近年来在理解 SLC 转运体功能的结构和分子基础以及调节 SLC 表达的途径和机制方面取得的进展，并描述了这些新见解为发现 SLC 转运体增强剂带来的机遇。最后，我们强调了各种方法所面临的挑战，并就未来可能有助于寻找具有治疗潜力的 SLC 增强剂的方向提供了一些思考。
