Two‐pore channels (TPCs) have been a hot topic in recent literature. Their involvement in various diseases such as viral infections and cancer is of great interest for drug research. Due to their localization in the endolysosomal system and the lack of cell‐permeable activators, complex techniques were required for studying channel functions. Here, we review the first published lipophilic small‐molecule activators of TPCs. In independent high‐throughput screens, several new agonists were discovered, which now allow simple and fast investigation of TPCs in more detail in intact cells and in vivo. Zhang et al. identified tricyclic and phenothiazine antidepressants as TPC1 and TPC2 activators by screening a library of approved drugs. In contrast, Gerndt et al. screened an extensive compound library with mostly new chemotypes and drug structures. The latter resulted in two structurally distinct high‐affinity agonists, which are able to selectively activate TPC2 in either an NAADP‐ or PI(3,5)P₂‐like manner. Here, we discuss the advantages and drawbacks of the identified molecules and their structural features. The versatility by which TPCs can be activated indicates many opportunities for future studies.

中文翻译：

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亲脂性两孔通道激动剂的发现。

在最近的文献中，双孔通道（TPC）一直是热门话题。他们参与各种疾病，例如病毒感染和癌症，对药物研究非常感兴趣。由于它们位于溶酶体系统中，并且缺乏细胞渗透性激活剂，因此研究通道功能需要复杂的技术。在这里，我们回顾了TPCs首次公开发表的亲脂性小分子活化剂。在独立的高通量筛选中，发现了几种新的激动剂，这些激动剂现在可以在完整细胞和体内更简单，更快速地研究TPC 。张等。通过筛选批准的药物库，鉴定出三环和吩噻嗪抗抑郁药为TPC1和TPC2激活剂。相反，Gerndt等。筛选了一个具有新化学型和药物结构的广泛化合物库。后者产生了两个结构上不同的高亲和力激动剂，它们能够以类似NAADP或PI（3,5）P ₂的方式选择性激活TPC2 。在这里，我们讨论识别出的分子及其结构特征的优缺点。激活TPC的多功能性为将来的研究提供了许多机会。