海德堡大学Tobias P. Dick研究小组在研究中取得进展。他们的研究报道了四硫酸锌中心对质子泵抑制剂雷贝拉唑的位点特异性激活。2025年2月20日出版的《自然-化学》杂志发表了这项成果。

采用化学蛋白质组学方法，研究组发现质子泵抑制剂雷贝拉唑选择性地与锌结合蛋白形成共价偶联物。通过对DENR（一种带有C4锌离子的蛋白）的研究，小组发现雷别拉唑被锌离子激活，随后结合到锌配位半胱氨酸上。结果表明，在锌配位球内，药物结合、活化和偶联发生迅速。最后，课题组提供的证据表明，其他质子泵抑制剂可以以同样的方式被激活。研究组得出结论，锌作为路易斯酸，无需低pH值，促进非酸性环境中质子泵抑制剂的活化和偶联。

据了解，质子泵抑制剂已经成为全球最畅销的药物。质子泵抑制剂是在酸性环境中被质子化激活的前药，通过共价修饰胃质子泵来抑制胃酸分泌。尽管它们的主题广泛，但非酸性环境中的其他激活机制和潜在靶蛋白仍然知之甚少。

附：英文原文

Title: Site-specific activation of the proton pump inhibitor rabeprazole by tetrathiolate zinc centres

Author: Marker, Teresa, Steimbach, Raphael R., Perez-Borrajero, Cecilia, Luzarowski, Marcin, Hartmann, Eric, Schleich, Sibylle, Pastor-Flores, Daniel, Espinet, Elisa, Trumpp, Andreas, Teleman, Aurelio A., Grter, Frauke, Simon, Bernd, Miller, Aubry K., Dick, Tobias P.

Issue&Volume: 2025-02-20

Abstract: Proton pump inhibitors have become top-selling drugs worldwide. Serendipitously discovered as prodrugs that are activated by protonation in acidic environments, proton pump inhibitors inhibit stomach acid secretion by covalently modifying the gastric proton pump. Despite their widespread use, alternative activation mechanisms and potential target proteins in non-acidic environments remain poorly understood. Employing a chemoproteomic approach, we found that the proton pump inhibitor rabeprazole selectively forms covalent conjugates with zinc-binding proteins. Focusing on DENR, a protein with a C4 zinc cluster (that is, zinc coordinated by four cysteines), we show that rabeprazole is activated by the zinc ion and subsequently conjugated to zinc-coordinating cysteines. Our results suggest that drug binding, activation and conjugation take place rapidly within the zinc coordination sphere. Finally, we provide evidence that other proton pump inhibitors can be activated in the same way. We conclude that zinc acts as a Lewis acid, obviating the need for low pH, to promote the activation and conjugation of proton pump inhibitors in non-acidic environments.

DOI: 10.1038/s41557-025-01745-8

Source: https://www.nature.com/articles/s41557-025-01745-8