DNA-modularized construction of bivalent ligands precisely regulates receptor binding and activation

Great interest is focused on the construction of bivalent ligands, where the spacer is crucial to coordinate the distance and orienta-tion of two pharmacophores for optimal biological effects. Current strategies rely on polymers as spacers but suffer from the paucity of structural precision and variability with time-consuming ligation procedures. Herein, we originate a DNA-modularized strategy where pharmacophores are modularly modified with the protecting groups used for automatic DNA synthesis while natural deoxynu-cleotides serve as spacers. By programmably regulating the number and permutation of the bridged DNA spacer, the two pharmaco-phores are adjusted with a defined distance and versatile orienta-tion. Using this strategy, we successfully constructed a reservoir of bivalent ligands containing an orthosteric agonist and an allosteric modulator, exhibiting a single-nucleotide difference in the selective activation of muscarinic acetylcholine receptors. Our strategy opens a new avenue for the precise construction and efficient screening of bivalent ligands toward a myriad of biomedical applications.

Automated summary

There is great interest in the construction of bivalent ligands, which requires an effective spacer to coordinate the distance and orientation of two pharmacophores. Current strategies using polymers as spacers lack structural precision and variability due to time-consuming ligation procedures. In this study, a DNA-modularized strategy is proposed, using natural deoxynucleotides as spacers and programmable regulation of the bridged DNA spacer, allowing for precise adjustment of distance and orientation of two pharmacophores. This strategy has been successfully applied to construct a reservoir of bivalent ligands for biomedical applications.