Abstract

Many cellular processes in living organisms are controlled by intricate regulatory networks formed by relatively few proteins capable of switching between homo- and heterooligomeric assemblies or mono- and bivalent states through noncovalent interactions.1 Motivated by mimicking these natural complexes, we focused on the macrocyclic host cucurbit[8]uril (CB[8]), which is characterized by its unique ability to form 1:2 hetero- or homodimeric inclusion complexes with a variety of guests.2 Of particular interest is the CB[8]-bipyridinium pair, a supramolecular switch that allows for further implementation of dynamic behavior due to its sensitivity to external stimuli.3 In this context, to the best of our knowledge, the use of the CB[8]-bipyridinium pair to reversibly control the dimerization and the biological activity of functional peptides has barely been explored. In this work, we demonstrate that the conjugation of a 4,4′-bipyridinium scaffold to the basic region of the GCN4 bZip transcription factor4 can be exploited to control the dimerization of the conjugate by forming a supramolecular complex with CB[8].5 Remarkably, this complex can specifically recognize its target dsDNA, and its binding can be reversibly disrupted by disassembling the host−guest complex upon application of external stimuli. 1. A. Reményi, H. R. Schöler, M. Wilmanns. Nat. Struct. Mol. Biol. 2004, 11, 812.2. S. J. Barrow, S. Kasera, M. J. Rowland, J. del Barrio, O. A. Scherman. Chem. Rev. 2015, 115, 12320.3. E. Pazos, P. Novo, C. Peinador, A. E. Kaifer, M. D. García. Angew. Chem. Int. Ed. 2019, 58, 403.4. P. Cortón, P. Novo, V. López-Sobrado, M. D. García, C. Peinador, E. Pazos. Synthesis 2020, 52, 537.5. P. Novo, M. D. García, C. Peinador, E. Pazos. Bioconj. Chem. 2021, 32, 507.