Demethylation of an artificial hydrogenase agent for prolonged CO release and enhanced anti-tau aggregation activity.

Carbon monoxide (CO) plays an important role in signaling in cells, making its use as a therapeutic tool highly intriguing. Reduced burst emissions are important to avoid the cytotoxicity and tissue damage caused by CO. Here, we developed a stable diiron carbonyl [FeFe] hydrogenase agent that enables prolonged CO release activity (half-life of over 9 h) in cells. The integrated analysis allowed the identification of the key intermediate sites and CO accumulations with subcellular resolution. We observed that the [FeFe] complex was enriched in neurons with S-methyl bond rupture. Furthermore, the [FeFe] complex efficiently reduced the aggregation of tau proteins (49.3% reduction) and showed superior biocompatibility in nerve cells (∼ 95% survival).