Bridging or exchanging partners? A supramolecular perspective on bifunctional molecules and their potential for...

Bifunctional molecules are commonly regarded as proximity-inducing compounds (PICs) that bridge two proteins to generate novel biological outcomes. Here, we highlight a distinct and emerging subclass, termed partner-exchanging molecules (PEMs), which cannot bind both protein partners simultaneously. Instead, they act through a partner-swapping mechanism, enabling one protein to unnaturally activate another. This perspective examines their mechanisms of action and surveys potential applications such as protein sensing, prodrug activation, controlled release, and the reconfiguration of intracellular signaling. Because PEMs offer a simple route to build triggerable enzymes, we further discuss them in the context of artificial zymogens, emphasizing their promise to mediate activation of therapeutic proenzyme systems via non-enzyme proteins and to render native enzymes triggerable in cells. By positioning PEMs as a conceptual link between bifunctional molecules and artificial zymogens, we aim to broaden our understanding of bifunctional regulators and expand the scope of artificial proenzyme design.