Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
J Control Release. 2022 Sep;349:304-314. doi: 10.1016/j.jconrel.2022.07.001. Epub 2022 Jul 9.
Hydrogen sulfide (HS) has attracted significant attention as a seed in drug development. However, HS is toxic and induces lethal acute intoxication. Here, we developed methemoglobin (metHb)-albumin clusters as detoxifying agents for HS intoxication, which were designed based on the inherent binding property of metHb with HS. The metHb-albumin clusters comprising an autoxidized ferric Hb center wrapped covalently with an average of three human serum albumins showed a similar HS binding affinity to that of naked metHb. Owing to the HS binding capability, metHb-albumin clusters suppressed cell death induced by HS exposure while maintaining mitochondrial function in H9c2 cells. In addition, lethal HS intoxication model mice were rescued by a single administration of metHb-albumin clusters, resulting from the recovery of cytochrome c oxidase activity. Furthermore, the metHb-albumin clusters possessed essential characteristics, such as adequate pharmacokinetic properties and biocompatibility, for their use as detoxifying agents against HS intoxication. In conclusion, the results obtained in this study suggest that metHb-albumin clusters are promising detoxifying agents for HS intoxication and that harnessing the inherent HS binding properties of metHb is an innovative approach to develop detoxifying agents for HS intoxication.
硫化氢 (HS) 作为药物研发的新靶点引起了广泛关注。然而，HS 具有毒性，并会导致致命的急性中毒。在这里，我们开发了高铁血红蛋白 (metHb)-白蛋白簇作为 HS 中毒的解毒剂，这是基于 metHb 与 HS 的固有结合特性设计的。metHb-白蛋白簇由一个自氧化的三价铁 Hb 中心共价包裹平均三个人类血清白蛋白组成，其 HS 结合亲和力与裸露的 metHb 相似。由于具有 HS 结合能力，metHb-白蛋白簇在维持 H9c2 细胞线粒体功能的同时，抑制了由 HS 暴露引起的细胞死亡。此外，通过单次给予 metHb-白蛋白簇，可拯救致死性 HS 中毒模型小鼠，这是由于细胞色素 c 氧化酶活性的恢复所致。此外，metHb-白蛋白簇具有足够的药代动力学特性和生物相容性等基本特征，可用作 HS 中毒的解毒剂。总之，本研究结果表明，metHb-白蛋白簇是一种有前途的 HS 中毒解毒剂，利用 metHb 的固有 HS 结合特性是开发 HS 中毒解毒剂的一种创新方法。
