4-Hhydroxyproline has been anchored to a polystyrene resin through click chemistry, and the resulting catalyst has been successfully applied to the direct aldol reaction in water. The high hydrophobicity of the resin and the presence of water are key to ensuring high stereoselectivity, whereas yield can be increased by using catalytic amounts of DiMePEG. This effect has been further demonstrated by the inefficiency of a homogeneous, more polar analogue.

A new functional polymer where proline is bonded to polystyrene through a 1,2,3-triazole linker depicts characteristics targeted for an artificial aldolase. In spite of the hydrophobicity of the polymer backbone, the resin swells in water with building of an aqueous microenvironment. This property, arising from the formation of a hydrogen-bond network connecting the proline and 1,2,3-triazole fragments, is translated into a very high catalytic activity and enantioselectivity toward direct aldol reactions in water.

Light-regulated drugs allow remotely photoswitching biological activity and enable plausible therapies based on small molecules. However, only freely diffusible photochromic ligands have been shown to work directly in endogenous receptors and methods for covalent attachment depend on genetic manipulation. Here we introduce a chemical strategy to covalently conjugate and photoswitch the activity of endogenous proteins and demonstrate its application to the kainate receptor channel GluK1. The approach is based on photoswitchable ligands containing a short-lived, highly reactive anchoring group that is targeted at the protein of interest by ligand affinity. These targeted covalent photoswitches (TCPs) constitute a new class of light-regulated drugs and act as prosthetic molecules that photocontrol the activity of GluK1-expressing neurons, and restore photoresponses in degenerated retina. The modularity of TCPs enables the application to different ligands and opens the way to new therapeutic opportunities.