Catenation Enhances Potency of a Bioactive Cyclopeptide

While mechanically interlocked molecules have revolutionized molecular machines and materials science, their potential in biomedicine remains largely underexplored. Artificial topological entanglement is often assumed to compromise bioactivity, restricting most biomedical applications to prodrug systems. Here, we challenge this assumption by showing that mechanical interlocking can be harnessed to enhance biological performance. We synthesize [2]-and [3]catenanes derived from a bioactive cyclopeptide and show that catenation modulates target binding affinity, significantly improves cellular uptake, and retains excellent plasma stability, collectively leading to a substantial gain in cellular potency. Integrated structural and computational analyses elucidate how mechanical interlocking tunes target binding and reveal the critical role of co-conformational flexibility. This work establishes mechanical bonds as versatile and active supramolecular design elements for developing biofunctional molecular machines.