Adhesive Photoswitch: Selective Photochemical Modulation of Enzymes under Physiological Conditions

Abstract

© 2017 American Chemical Society. We developed a water-soluble adhesive photoswitch (Gluen-Azo-SA, average n = 5) that selectively binds to a target enzyme and photochemically modulates its enzymatic activity even in cell lysates. Its design strategy features a photochromic azobenzene unit (Azo), which carries on one side an inhibitory motif for the target enzyme and on the other a glue part (Gluen) that utilizes its multiple guanidinium ion (Gu+) pendants for adhering onto the target surface. The target of Gluen-Azo-SA is carbonic anhydrase (CA) because sulfonamide (SA) derivatives, such as SA at the terminus of Gluen-Azo-SA, are known to bind selectively to the CA active site. The SA moiety, upon docking at the CA active site, possibly guides the connecting Gluen part to an oxyanion-rich area in proximity to the active site for adhesion, so that the conjugation between Gluen-Azo-SA and CA is ensured. With this geometry, the photochemical isomerization of the Azo unit likely generates a push-pull motion of SA, resulting in its docking and undocking at the active site of CA with the help of a competing substrate. Consequently, Gluen-Azo-SA can selectively photomodulate the enzymatic action of CA even in cell lysates. Azo-SA without Gluen can likewise suppress the enzymatic activity of CA by docking SA at its active site, but the resulting CA/Azo-SA conjugate, in contrast, does not respond to light.