Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Angew Chem Int Ed Engl. 2022 Jun 7;61(23):e202201698. doi: 10.1002/anie.202201698. Epub 2022 Apr 6.
Ionophores transport ions across biological membranes and have wide-ranging applications, but a platform for their rapid development does not exist. We report a platform for developing ionophores from metal-ion chelators, which are readily available with wide-ranging affinities and specificities, and structural data that can aid rational design. Specifically, we fine-tuned the binding affinity and lipophilicity of a Zn -chelating ligand by introducing silyl groups proximal to the Zn -binding pocket, which generated ionophores that performed better than most of the currently known Zn ionophores. Furthermore, these silicon-based ionophores were specific for Zn over other metals and exhibited better antibacterial activity and less toxicity to mammalian cells than several known Zn ionophores, including pyrithione. These studies establish rational design principles for the rapid development of potent and specific ionophores and a new class of antibacterial agents.
离子载体通过生物膜运输离子，具有广泛的应用，但目前还没有专门用于其快速开发的平台。我们报告了一种基于金属离子螯合剂开发离子载体的平台，这些螯合剂具有广泛的亲和力和特异性，并且具有可以辅助合理设计的结构数据。具体来说，我们通过在靠近 Zn 结合口袋的位置引入硅基，微调了一种与 Zn 结合的配体的结合亲和力和亲脂性，从而生成了比大多数目前已知的 Zn 离子载体性能更好的离子载体。此外，这些基于硅的离子载体对 Zn 具有特异性，优于其他金属，并且其抗菌活性和对哺乳动物细胞的毒性均低于包括吡啶硫酮在内的几种已知的 Zn 离子载体。这些研究为快速开发有效且具有特异性的离子载体和一类新型抗菌剂建立了合理的设计原则。
