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1.
Chem Sci ; 11(2): 429-434, 2020 Jan 14.
Article in English | MEDLINE | ID: mdl-32190263

ABSTRACT

Herein, we report a photoswitchable modulator for a nuclear hormone receptor that exerts its hormonal effects in a light-dependent fashion. The azobenzene AzoGW enables optical control of the farnesoid X receptor (FXR), a key regulator of hepatic bile acid, lipid and glucose metabolism. AzoGW was derived from the synthetic agonist GW4064 through an azologization strategy and is a metabolically stable, highly selective photoswitchable FXR agonist in its dark-adapted form. Upon irradiation, the thermally bistable 'photohormone' becomes significantly less active. Optical control of FXR was demonstrated in a luminescence reporter gene assay and through light-dependent reversible transcription modulation of FXR target genes (CYP7A1, Ostα, Ostß) in liver cells.

2.
Angew Chem Int Ed Engl ; 58(43): 15421-15428, 2019 10 21.
Article in English | MEDLINE | ID: mdl-31441199

ABSTRACT

Photopharmacology relies on ligands that change their pharmacodynamics upon photoisomerization. Many of these ligands are azobenzenes that are thermodynamically more stable in their elongated trans-configuration. Often, they are biologically active in this form and lose activity upon irradiation and photoisomerization to their cis-isomer. Recently, cyclic azobenzenes, so-called diazocines, have emerged, which are thermodynamically more stable in their bent cis-form. Incorporation of these switches into a variety of photopharmaceuticals could convert dark-active ligands into dark-inactive ligands, which is preferred in most biological applications. This "pharmacological sign-inversion" is demonstrated for a photochromic blocker of voltage-gated potassium channels, termed CAL, and a photochromic opener of G protein-coupled inwardly rectifying potassium (GIRK) channels, termed CLOGO.


Subject(s)
Azo Compounds/chemistry , G Protein-Coupled Inwardly-Rectifying Potassium Channels/agonists , Light , Potassium Channel Blockers/chemistry , Action Potentials/drug effects , Azo Compounds/pharmacology , Cyclization , Drug Design , G Protein-Coupled Inwardly-Rectifying Potassium Channels/genetics , G Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism , HEK293 Cells , Humans , Isomerism , Lidocaine/chemistry , Patch-Clamp Techniques , Potassium Channel Blockers/pharmacology , Thermodynamics
3.
Acc Chem Res ; 50(6): 1367-1374, 2017 06 20.
Article in English | MEDLINE | ID: mdl-28485577

ABSTRACT

Conjugation of DNA to proteins is increasingly used in academia and industry to provide proteins with tags for identification or handles for hybridization to other DNA strands. Assay technologies such as immuno-PCR and proximity ligation and the imaging technology DNA-PAINT require DNA-protein conjugates. In DNA nanotechnology, the DNA handle is exploited to precisely position proteins by self-assembly. For these applications, site-selective conjugation is almost always desired because fully functional proteins are required to maintain the specificity of antibodies and the activity of enzymes. The introduction of a bioorthogonal handle at a specific position of a protein by recombinant techniques provides an excellent approach to site-specific conjugation, but for many laboratories and for applications where several proteins are to be labeled, the expression of recombinant proteins may be cumbersome. In recent years, a number of chemical methods that target conjugation to specific sites at native proteins have become available, and an overview of these methods is provided in this Account. Our laboratory has investigated DNA-templated protein conjugation (DTPC), which offers an alternative approach to site-selective conjugation of DNA to proteins. The method is inspired by the concept of DNA-templated synthesis where functional groups conjugated to DNA strands are preorganized by DNA hybridization to dramatically increase the reaction rate. In DPTC, we target metal binding sites in proteins to template selective covalent conjugation reactions. By chelation of a DNA-metal complex with a metal binding site of the protein, an electrophile on a second DNA strand is aligned for reaction with a lysine side chain on the protein in the proximity of the metal binding site. The method is quite general because approximately one-third of all wild-type proteins contain metal-binding sites, including many IgG antibodies, and it is also applicable to His-tagged proteins. This emerging field provides direct access to site-selective conjugates of DNA to commercially available proteins. In this Account, we introduce these methods to the reader and describe current developments and future aspects.


Subject(s)
DNA/chemistry , Proteins/chemistry , Binding Sites , Substrate Specificity
4.
Org Biomol Chem ; 15(1): 76-81, 2016 Dec 20.
Article in English | MEDLINE | ID: mdl-27901161

ABSTRACT

G-protein coupled inwardly rectifying potassium (GIRK) channels are an integral part of inhibitory signal transduction pathways, reducing the activity of excitable cells via hyperpolarization. They play crucial roles in processes such as cardiac output, cognition and the coordination of movement. Therefore, the precision control of GIRK channels is of critical importance. Here, we describe the development of the azobenzene containing molecule VLOGO (Visible Light Operated GIRK channel Opener), which activates GIRK channels in the dark and is promptly deactivated when illuminated with green light. VLOGO is a valuable addition to the existing tools for the optical control of GIRK channels as it circumvents the need to use potentially harmful UV irradiation. We therefore believe that VLOGO will be a useful research tool for studying GIRK channels in biological systems.


Subject(s)
Azo Compounds/chemistry , Azo Compounds/pharmacology , G Protein-Coupled Inwardly-Rectifying Potassium Channels/agonists , G Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism , HEK293 Cells , Humans , Light , Patch-Clamp Techniques , Photochemical Processes/drug effects
5.
Org Biomol Chem ; 13(1): 185-98, 2015 Jan 07.
Article in English | MEDLINE | ID: mdl-25358438

ABSTRACT

Amides of 1,4-dihydropyridine (DHP) are activated by oxidation for acyl transfer to amines, alcohols and thiols. In the reduced form the DHP amide is stable towards reaction with amines at room temperature. However, upon oxidation with DDQ the acyl donor is activated via a proposed pyridinium intermediate. The activated intermediate reacts with various nucleophiles to give amides, esters, and thio-esters in moderate to high yields.


Subject(s)
Amides/chemistry , Dihydropyridines/chemistry , Biomimetics , Oxidation-Reduction , Phenethylamines/chemistry
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