spatiotemporally-controlled-nuclear-translocation-guests-living-cells

Spatiotemporally Controlled Nuclear Translocation of Guests in Living Cells Using Caged Molecular Glues as Photoactivatable Tags

The cell nucleus is one of the most important organelles as a subcellular drug-delivery target, since modulation of gene replication and expression is ...

University of Tokyo

We developed a water-soluble adhesive photoswitch (Glue-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 (Glue) that utilizes its multiple guanidinium ion (Gu) pendants for adhering onto the target surface. The target of Glue-Azo-SA is carbonic anhydrase (CA) because sulfonamide (SA) derivatives, such as SA at the terminus of Glue-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 Glue part to an oxyanion-rich area in proximity to the active site for adhesion, so that the conjugation between Glue-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, Glue-Azo-SA can selectively photomodulate the enzymatic action of CA even in cell lysates. Azo-SA without Glue 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.

Adhesive Photoswitch: Selective Photochemical Modulation of Enzymes under Physiological Conditions.

Molecular adhesion based on multivalent interactions plays essential roles in various biological processes. Hence, "molecular glues" that can adhere to biomolecules may modulate biomolecular functions and therefore can be applied to therapeutics. This tutorial review describes design strategies for developing adhesive motifs for biomolecules based on multivalent interactions. We highlight a guanidinium ion-based salt-bridge as a key interaction for adhesion to biomolecules and discuss the application of molecular glues for manipulation of biomolecular assemblies, drug delivery systems, and modulation of biomolecular functions.

Guanidinium-based "molecular glues" for modulation of biomolecular functions.

We developed dendritic caged molecular glues (Glue-R) as tags for nucleus-targeted drug delivery, whose multiple guanidinium ion (Gu) pendants are protected by an anionic photocleavable unit (butyrate-substituted nitroveratryloxycarbonyl; NVOC). Negatively charged Glue-R hardly binds to anionic biomolecules because of their electrostatic repulsion. However, upon exposure of Glue-R to UV light or near-infrared (NIR) light, the NVOC groups of Glue-R are rapidly detached to yield an uncaged molecular glue (Glue-R) that carries multiple Gu pendants. Because Gu forms a salt bridge with PO, Glue-R tightly adheres to anionic biomolecules such as DNA and phospholipids in cell membranes by a multivalent salt-bridge formation. When tagged with Glue-R, guests can be taken up into living cells via endocytosis and hide in endosomes. However, when the Glue-R tag is photochemically uncaged to form Glue-R, the guests escape from the endosome and migrate into the cytoplasm followed by the cell nucleus. We demonstrated that quantum dots (QDs) tagged with Glue-R can be delivered efficiently to cell nuclei eventually by irradiation with light.

Article	Year
Adhesive Photoswitch: Selective Photochemical Modulation of Enzymes under Physiological Conditions. Journal of the American Chemical Society\| PubMed ID: 28675032	2017
Guanidinium-based "molecular glues" for modulation of biomolecular functions. Chemical Society reviews\| PubMed ID: 29034942	2017
Caged Molecular Glues as Photoactivatable Tags for Nuclear Translocation of Guests in Living Cells. Journal of the American Chemical Society\| PubMed ID: 29381064	2018

Rina Mogaki

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