One‐Pot Self‐Assembly of Peptide‐Based Cage‐Type Nanostructures Using Orthogonal Ligations

Abstract

The designed arrangement of biomolecular entities within monodisperse nanostructures is an important challenge toward functional biomaterials. We report herein a method for the formation of water-soluble peptide-based cages using orthogonal ligation reactions-acylhydrazone condensation and thiol-maleimide addition. The results show that using preorganized cyclic peptides and heterobifunctional spacers as building blocks and a set of orthogonal and chemoselective ligation reactions enable cage formation in one pot from six components and through eight reactions. Molecular modelling simulations reveal the structural dynamics of these structures. Finally, we exploited the reactional dynamics of the acylhydrazone by demonstrating the controlled dissociation of the cage through directed component exchange.

Self‐Assembly of Functional Discrete Three‐Dimensional Architectures in Water

“…Formation of this assembly was underpinned by the thermodynamically favourable coiled‐coil interactions, with association of complementary CCDi‐A and CCDi‐B termini providing the driving force for self‐assembly of complementary charged hubs . Three‐dimensional structures have also been developed through the combination of cyclic peptides and heterobifunctional spacers, and can be manipulated for small‐molecule recognition …”

“…[179] Threedimensional structures have also been developed through the combination of cyclic peptides and heterobifunctional spacers, [180] and can be manipulated for small-molecule recognition. [181] Several different methods have been reported for the assembly of peptides into tetrahedral architectures.I n2 013, Jerala and co-workers reported formation of ap eptide tetrahedron from as ingle polypeptide chain containing twelve coiled-coil forming sections. [182] An alternative approach involving the combination of peptide building blocks with different symmetries was reported in 2015 by Arai and co-workers.…”

Growing Prospects of Dynamic Covalent Chemistry in Delivery Applications

“…79,80 We have used the fact that oximes are thermodynamically more stable than acylhydrazones to operate a directed acylhydrazone-to-oxime exchange reaction. 41,81,82 Using methoxyamine, we have been able to demonstrate the principle of chemically-triggered DNA decomplexation that results from the conversion of active cationic multivalent systems into inactive neutral assemblies through DCvC (Figure 9). 68…”

“…For instance, disulfide reduction can be triggered by the intracellular environment and lead to vector degradation and concomitant drug release . The cationic poly­(disulfide)­s of Matile were found to depolymerize rapidly within minutes after intracellular reduction, which minimized their toxicity. , Rapidly depolymerizing poly­(disulfide)­s enter cytosol where they release their cargo upon intracellular reduction, while slower depolymerizing poly­(disulfide)­s can transit to cell nuclei, thus showing the importance but also the vast opportunities given by tuning the thermodynamic features of reversible covalent reactions. , We have used the fact that oximes are thermodynamically more stable than acylhydrazones to operate a directed acylhydrazone-to-oxime exchange reaction. ,, Using methoxyamine, we have been able to demonstrate the principle of chemically triggered DNA decomplexation that results from the conversion of active cationic multivalent systems into inactive neutral assemblies through DCvC (Figure ). …”

Selbstorganisation von funktionellen diskreten dreidimensionalen Architekturen in Wasser

“…Die Bildung dieser Anordnung wurde durch die thermodynamisch günstigen Coiled‐Coil‐Wechselwirkungen untermauert, wobei eine Assoziation der komplementären CCDi‐A‐ und CCDi‐B‐Termini die Triebkraft für die Selbstorganisation von komplementär geladenen Knotenpunkten lieferte . Außerdem wurden durch die Kombination cyclischer Peptide und heterodifunktioneller Abstandhalter 3D‐Strukturen entwickelt, die für eine Erkennung kleiner Moleküle manipuliert werden können …”