The receptor binding domain (RBD) of the spike glycoprotein of the coronavirus SARS‐CoV‐2 (CoV2‐S) binds to the human angiotensin‐converting enzyme 2 (ACE2) representing the initial contact point for leveraging the infection cascade. We used an automated selection process and identified an aptamer that specifically interacts with CoV2‐S. The aptamer does not bind to the RBD of CoV2‐S and does not block the interaction of CoV2‐S with ACE2. Nevertheless, infection studies revealed potent and specific inhibition of pseudoviral infection by the aptamer. The present study opens up new vistas in developing SARS‐CoV2 infection inhibitors, independent of blocking the ACE2 interaction of the virus, and harnesses aptamers as potential drug candidates and tools to disentangle hitherto inaccessible infection modalities, which is of particular interest in light of the increasing number of escape mutants that are currently being reported.

A recent trend in DNA nanotechnology consists of the assembly of architectures with dynamic properties that can be regulated by employing external stimuli. Reversible processes are important for implementing molecular motion into DNA architectures as they allow for the regeneration of the original state. Here we describe two different approaches for the reversible switching of a double-stranded DNA rotaxane architecture from a stationary pseudorotaxane mode into a state with movable components. Both states only marginally differ in their respective topologies but their mechanical properties are fundamentally different. In the two approaches, the switching operation is based on strand-displacement reactions. One of them employs toehold-extended oligodeoxynucleotides whereas in the other one the switching is achieved by light-irradiation. In both cases, multiple back and forth switching between the stationary and the mobile states was achieved in nearly quantitative fashion. The ability to reversibly operate mechanical motion in an interlocked DNA nanostructure opens exciting new avenues in DNA nanotechnology.