A class of rotaxane is created, not by encapsulating a conventional linear thread, but rather by wrapping a large cucurbit[10]­uril macrocycle about a three-dimensional, cylindrical, nanosized, self-assembled supramolecular helicate as the axle. The resulting pseudo-rotaxane is readily converted into a proper interlocked rotaxane by adding branch points to the helicate strands that form the surface of the cylinder (like branches and roots on a tree trunk). The supramolecular cylinder that forms the axle is itself a member of a unique and remarkable class of helicate metallo-drugs that bind Y-shaped DNA junction structures and induce cell death. While pseudo-rotaxanation does not modify the DNA-binding properties, proper, mechanically-interlocked rotaxanation transforms the DNA-binding and biological activity of the cylinder. The ability of the cylinder to de-thread from the rotaxane (and thus to bind DNA junction structures) is controlled by the extent of branching: fully-branched cylinders are locked inside the cucurbit[10]­uril macrocycle, while cylinders with incomplete branch points can de-thread from the rotaxane in response to competitor guests. The number of branch points can thus afford kinetic control over the drug de-threading and release.

The untranslated regions (UTRs) of viral genomes contain av ariety of conserved yet dynamic structures crucial for viral replication, providing drug targets for the development of broad spectrum anti-virals.W ecombine in vitro RNA analysis with molecular dynamics simulations to build the first 3D models of the structure and dynamics of key regions of the 5' UTR of the SARS-CoV-2 genome.F urthermore,w e determine the binding of metallo-supramolecular helicates (cylinders) to this RNAs tructure.T hese nano-sizea gents are uniquely able to thread through RNAjunctions and we identify their binding to a3 -base bulge and the central cross 4-way junction located in stem loop 5. Finally,w es how these RNAbinding cylinders suppress SARS-CoV-2 replication, highlighting their potential as novel anti-viral agents.

The untranslated regions (UTRs) of viral genomes contain a variety of conserved yet dynamic structures crucial for viral replication, providing drug targets for the development of broad spectrum anti‐virals. We combine in vitro RNA analysis with molecular dynamics simulations to build the first 3D models of the structure and dynamics of key regions of the 5′ UTR of the SARS‐CoV‐2 genome. Furthermore, we determine the binding of metallo‐supramolecular helicates (cylinders) to this RNA structure. These nano‐size agents are uniquely able to thread through RNA junctions and we identify their binding to a 3‐base bulge and the central cross 4‐way junction located in stem loop 5. Finally, we show these RNA‐binding cylinders suppress SARS‐CoV‐2 replication, highlighting their potential as novel anti‐viral agents.

The untranslated regions (UTRs) of viral genomes contain a variety of conserved yet dynamic structures crucial for viral replication, providing drug targets for the development of broad spectrum anti-virals. We combine in vitro RNA analysis with Molecular Dynamics simulations to build the first 3D models of the structure and dynamics of key regions of the 5-prime UTR of the SARS-CoV-2 genome. Furthermore, we determine the binding of metallo-supramolecular helicates (cylinders) to this RNA structure. These nano-size agents are uniquely able to thread through RNA junctions and we identify their binding to a 3-base bulge and the central cross 4-way junction located in the stem loop 5. Finally, we show these RNA-binding cylinders suppress SARS-CoV-2 replication, highlighting their potential as novel anti-viral agents.