Department of Cell Physiology and Molecular Biophysics, and Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
Department of Chemistry and Biochemistry, Utah State University, Logan, UT, USA.
Biochim Biophys Acta Mol Basis Dis. 2021 Jun 1;1867(6):166115. doi: 10.1016/j.bbadis.2021.166115. Epub 2021 Mar 9.
Connexins are membrane proteins involved directly in cell-to-cell communication through the formation of gap-junctional channels. These channels result from the head-to-head docking of two hemichannels, one from each of two adjacent cells. Undocked hemichannels are also present at the plasma membrane where they mediate the efflux of molecules that participate in autocrine and paracrine signaling, but abnormal increase in hemichannel activity can lead to cell damage in disorders such as cardiac infarct, stroke, deafness, cataracts, and skin diseases. For this reason, connexin hemichannels have emerged as a valid therapeutic target. Know small molecule hemichannel inhibitors are not ideal leads for the development of better drugs for clinical use because they are not specific and/or have toxic effects. Newer inhibitors are more selective and include connexin mimetic peptides, anti-connexin antibodies and drugs that reduce connexin expression such as antisense oligonucleotides. Re-purposed drugs and their derivatives are also promising because of the significant experience with their clinical use. Among these, aminoglycoside antibiotics have been identified as inhibitors of connexin hemichannels that do not inhibit gap-junctional channels. In this review, we discuss connexin hemichannels and their inhibitors, with a focus on aminoglycoside antibiotics and derivatives of kanamycin A that inhibit connexin hemichannels, but do not have antibiotic effect.
间隙连接蛋白是一种直接参与细胞间通讯的膜蛋白，通过形成缝隙连接通道来实现。这些通道是由两个相邻细胞的两个半通道头对头对接形成的。未对接的半通道也存在于质膜上，它们介导参与自分泌和旁分泌信号的分子外流，但半通道活性的异常增加会导致心脏梗死、中风、耳聋、白内障和皮肤病等疾病中的细胞损伤。因此，间隙连接蛋白半通道已成为一个有效的治疗靶点。已知小分子半通道抑制剂不是开发用于临床的更好药物的理想先导化合物，因为它们不具有特异性和/或具有毒性作用。较新的抑制剂更具选择性，包括间隙连接模拟肽、抗间隙连接蛋白抗体以及降低间隙连接蛋白表达的药物，如反义寡核苷酸。重新定位的药物及其衍生物也很有前途，因为它们在临床应用方面有大量经验。其中，氨基糖苷类抗生素已被确定为不抑制缝隙连接通道的间隙连接蛋白半通道抑制剂。在这篇综述中，我们讨论了间隙连接蛋白半通道及其抑制剂，重点介绍了氨基糖苷类抗生素和卡那霉素 A 的衍生物，它们抑制间隙连接蛋白半通道，但没有抗生素作用。
