Sequence-selective encapsulation and protection of long peptides by a self-assembled Fe$^\text{II}$$_{8}$L$_{6}$ cubic cage

Self-assembly offers a general strategy for the preparation of large, hollow high-symmetry structures. Although biological capsules, such as virus capsids, are capable of selectively recognizing complex cargoes, synthetic encapsulants have lacked the capability to specifically bind large and complex biomolecules. Here we describe a cubic host obtained from the self-assembly of Fe$^\text{II}$ and a zinc-porphyrin-containing ligand. This cubic cage is flexible and compatible with aqueous media. Its selectivity of encapsulation is driven by the coordination of guest functional groups to the zinc porphyrins. This new host thus specifically encapsulates guests incorporating imidazole and thiazole moieties, including drugs and small proteins. Once encapsulated, the reactivity of a peptide is dramatically altered: Encapsulated peptides are protected from trypsin hydrolysis, whereas physicochemically similar peptides that do not bind are cleaved.This work was supported by the UK Engineering and Physical Sciences Research Council (EPSRC EP/M008258/1). The authors thank the Department of Chemistry NMR facility (University of Cambridge), Balasubramanian Group for use of the HPLC, and Dr. J. A. Foster for providing 5-hydroxypicolinaldehyde employed in the initial experiments of the project. J. M. acknowledges postdoctoral fellowship support from Fundación Ramón Areces