Inhibition of Connexin Hemichannels by New Amphiphilic Aminoglycosides without Antibiotic Activity,ACS Medicinal Chemistry Letters

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Inhibition of Connexin Hemichannels by New Amphiphilic Aminoglycosides without Antibiotic Activity
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-06-19 00:00:00 , DOI: 10.1021/acsmedchemlett.8b00158
Madher N. AlFindee _{1,

2} , Yagya P. Subedi ₁ , Mariana C. Fiori ₃ , Srinivasan Krishnan ₃ , Abbey Kjellgren _{3,

4} , Guillermo A. Altenberg ₃ , Cheng-Wei T. Chang ₁

Affiliation

Connexins hemichannels (HCs) from adjacent cells form gap junctional channels that mediate cell-to-cell communication. Abnormal opening of “free” undocked HCs can produce cell damage and participate in the mechanism of disorders such as cardiac infarct, stroke, deafness, skin diseases, and cataracts. Therefore, inhibitors of connexin HCs have great pharmacological potential. Antibiotic aminoglycosides (AGs) have been recently identified as connexin HC inhibitors, but their antibiotic effect is an issue for the treatment of disorders where infections do not play a role. Herein, we synthesized and tested several amphiphilic AGs without antibiotic effect for their inhibition against connexin HCs, using a newly developed cell-based bacterial growth complementation assay. Several leads with superior potency than the parent compound, kanamycin A, were identified. Unlike traditional AGs, these amphiphilic AGs are not bactericidal and are not toxic to mammalian cells, making them better than traditional AGs as HC inhibitors for clinical use and other applications.

中文翻译：

没有抗生素活性的新型两亲氨基糖苷对连接蛋白半通道的抑制作用

来自相邻细胞的连接蛋白半通道（HCs）形成介导细胞间通讯的间隙连接通道。“自由的”未对接的HCs的异常开放会产生细胞损伤，并参与诸如心肌梗塞，中风，耳聋，皮肤病和白内障等疾病的机制。因此，连接蛋白HCs的抑制剂具有很大的药理潜力。抗生素氨基糖苷类（AGs）最近已被确定为连接蛋白HC抑制剂，但其抗生素作用是治疗感染不起作用的疾病的一个问题。在这里，我们使用一种新开发的基于细胞的细菌生长互补测定法，合成并测试了几种不具有抗生素作用的两亲性AGs对连接蛋白HCs的抑制作用。有几条比母体化合物卡那霉素A具有更高效力的潜在客户，被确定。与传统的AG不同，这些两亲性AG不具有杀菌作用，并且对哺乳动物细胞无毒，因此它们在临床和其他应用中作为HC抑制剂比传统AG更好。

更新日期：2018-06-19

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