A dual-metal catalyzed sequential cascade reaction in an engineered protein cage

In this study, we describe the creation of an artificial protein cage housing a dual metal-tagged guest protein that catalyzes a linear, two-step sequential cascade reaction. The guest protein consists of a fusion protein of HaloTag and monomeric rhizavidin. Inside the protein capsid, we establish a ruthenium-catalyzed alloc-deprotection followed by a gold-catalyzed ring-closing hydroamination reaction that leads to indoles and phenanthridines with an overall yield of up to 67% in aqueous solutions. Furthermore, we show that the encapsulation stabilizes the metal catalysts against deactivation by air, proteins and cell lysate.