Ligand-Directed Caging Enables the Control of Endogenous DNA Alkyltransferases Activity with Light inside Live Cells
The control of endogenous proteins activity with light inside live cells is helpful for the high spatiotemporal probing of their dynamic roles. Herein, we report the first small-molecule-ligand-directed caging approach to control the endogenous human O 6 -alkylguanine-DNA alkyltransferases (AGT) activity with light, and the caged AGT is constructed from the native intracellular AGT.
The photo-responsive O 6 -benzylguanine derivative O 6 -NBG3 is developed to site-specifically cage the AGT’s catalytic cysteine residue, and the light irradiation on-demand restores AGT’s activity in vitro, in bacteria, and in mammalian cells. With O 6 -NBG3, the alkylated AGT is dealkylated for the first time to recover the DNA repair activity in breast cancer MCF-7 cells by the dose-dependent light irradiation. This decaging strategy enables the localized modulation of endogenous AGT activity in high temporal precision without genetic engineering, which holds great potential for therapeutic applications.
Interspecies-Extrapolated Biotic Ligand Model to Predict Arsenate Toxicity to Terrestrial Plants with Consideration of Cell Membrane Surface Electrical Potential
Arsenic is a metalloid that is highly toxic to living organisms in the environment. In this study, toxicity caused by inorganic arsenate (As(V)) to terrestrial plants, such as barley Hordeum vulgare and wheat Triticum aestivum, was predicted using the existing biotic ligand model (BLM) for bioluminescent Aliivibrio fischeri via interspecies extrapolation. Concurrently, the concept of cell plasma membrane electrical potential (Ψ0) was incorporated into the extrapolated BLM to improve the model predictability in the presence of major cations such as Ca2+. The 50% effective As(V) toxicity (EC50{HAsO42-}) to H. vulgare decreased from 45.1 ± 4.34 to 15.0 ± 2.60 µM as Ca2+ concentration increased from 0.2 to 20 mM owing to the accumulation of H2AsO4– and HAsO42- on the cell membrane surface. The extrapolated BLM, which only considered inherent sensitivity, explained well the alteration of As(V) toxicity to H. vulgare and T. aestivum by Ca2+ with in an order of magnitude, when considering a linear relationship between Ψ0 and EC50{HAsO42-}.
Development of novel potent ligands for GPR85, an orphan G protein-coupled receptor expressed in the brain
GPR85 is a member of the G protein-coupled receptor and is a super-conserved receptor expressed in the brain sub-family (Super Conserved Receptor Expressed in Brain; SREB) with GPR27 and GPR173. These three receptors are “orphan receptors”; however, their endogenous ligands have not been identified. SREB has garnered the interest of many scientists because it is expressed in the central nervous system and is evolutionarily conserved. In particular, brain mass is reported to be increased and learning and memory are improved in GPR85 knockout mice (Matsumoto et al. 2008). In this study, we characterized newly synthesized compounds using a GPR85-Gsα fusion protein and the [35 S]GTPγS binding assay and identified novel GPR85 inverse-agonists with IC50 values of approximately 1 μM.
To analyze the neurochemical character of the compounds and investigate the physiological significance of GPR85, we used cerebellar Purkinje cells expressing GPR85 and an electrophysiological technique. Based on the results, the inverse-agonist compound for GPR85 modulated potassium channel opening. Together with the results of previous gene analysis of GPR85, we expect that the development of the GPR85 ligand will provide new insights into a few types of neurological disorders.
Highly stable actinide(III) complexes supported by doubly aromatic ligands
Owing to the electron-deficient nature of boron atoms, the structures and properties of boron clusters can be enriched by doping various metal atoms, including lanthanide metal atoms. Nevertheless, the viability of actinide analogues has not been fully elucidated up to now. Here we demonstrate a series of highly stable low-valent actinide(III) boron clusters AnB7 (An = Pa, U, Np, and Pu) using first-principles calculations. The predicted global minimum structures of all the AnB7 complexes possess half-sandwich geometries with C6v symmetry and belong to MIII[B7]3--type species. In each AnB7 species, the B73- ligand possesses double aromaticity features with six delocalized π electrons and six delocalized σ electrons.
Bonding analysis shows that although there is a substantial contribution of electrostatic interaction in each cluster, covalent interaction is responsible for the stability of AnB7. All the AnB7 species show significantly high formation energies, especially for NpB7, which is in line with the stronger Np-B covalent bonds. In addition, the simulated photoelectron spectroscopy analysis confirms the high electronic stability of neutral AnB7. These results imply that these ultrastable actinide(III) complexes are accessible in the gas phase at room temperature. This work may provide a theoretical basis for the design of highly stable boron-based nanomaterials as well as preparation of low-valent actinide complexes.
Novel Derivatives of diphenyl-1,3,4-oxadiazol as Ligands of Benzodiazepine Receptors; Synthesize, Binding Assay and Pharmacological Evaluation
Benzodiazepines (BZD) are among the main classes of tranquilizing drugs, bearing much less toxicity compared to other drugs acting on the CNS. Considering the pharmacophore model of BZD binding to GABA-A receptor, novel diphenyl 1,3,4-oxadiazole compounds as BZD ligands were designed. The compounds were synthesized and structurally confirmed using LCMS, IR and NMR techniques. We investigated the affinity of the compounds to BZD receptors using radioligand [3H]-flumazenil by in-vitro studies. In addition, sedative-hypnotic, anxiety, anticonvulsant, muscle relaxant, memory impairment, and motor coordination activities of the synthesized compounds were evaluated using in–vivo studies.
Based on in-vitro studies, compounds 7i and 7j were the most potent with IC50 values of 1.54 and 1.66 nM respectively. In-vivo studies showed that compound 7i has the highest impact on increased sedation, muscle relaxation, and decreased anxiety and these observations were antagonized by flumazenil. Compounds 7e and 7i were the most potent anticonvulsant agents among synthesized compounds in both MES and PTZ induced seizure tests. All synthesized compounds significantly decreased latency to fall in the Rotarod test but none of them had a significant impact on the memory impairment test.
Colloidal-ALD-Grown Hybrid Shells Nucleate via a Ligand-Precursor Complex
Colloidal atomic layer deposition (c-ALD) enables the growth of hybrid organic-inorganic oxide shells with tunable thickness at the nanometer scale around ligand-functionalized inorganic nanoparticles (NPs). This recently developed method has demonstrated improved stability of NPs and of their dispersions, a key requirement for their application. Nevertheless, the mechanism by which the inorganic shells form is still unknown, as is the nature of multiple complex interfaces between the NPs, the organic ligands functionalizing the surface, and the shell.
THPTA ligand, 100 mg | ||||
| F4050 | Lumiprobe | 100 mg | 80.4 EUR | |
THPTA ligand, 1 g | ||||
| I4050 | Lumiprobe | 1 g | 366 EUR | |
THPTA ligand, 500 mg | ||||
| H4050 | Lumiprobe | 500 mg | 259.2 EUR | |
Flt3 ligand Antibody | ||||
| DF7676 | Affbiotech | 200ul | 420 EUR | |
rHu RANK-Ligand | ||||
| AK8283-0002 | Akron Biotech | 2µg | Ask for price | |
rHu RANK-Ligand | ||||
| AK8283-0010 | Akron Biotech | 10µg | Ask for price | |
rHu RANK-Ligand | ||||
| AK8283-0100 | Akron Biotech | 100µg | Ask for price | |
rHu RANK-Ligand | ||||
| AK8283-1000 | Akron Biotech | 1mg | Ask for price | |
rHu CD40 Ligand | ||||
| AK9162-0010 | Akron Biotech | 10µg | Ask for price | |
rHu CD40 Ligand | ||||
| AK9162-0050 | Akron Biotech | 50µg | Ask for price | |
rHu CD40 Ligand | ||||
| AK9162-0100 | Akron Biotech | 100µg | Ask for price | |
rHu CD40 Ligand | ||||
| AK9162-1000 | Akron Biotech | 1mg | Ask for price | |
Fas Ligand Antibody | ||||
| AF5333 | Affbiotech | 200ul | 420 EUR | |
Fas Ligand Antibody | ||||
| AF0157 | Affbiotech | 200ul | 420 EUR | |
Flt3 Ligand antibody | ||||
| 70R-FR009 | Fitzgerald | 50 ug | 327.6 EUR | |
Flt3 Ligand antibody | ||||
| 70R-7181 | Fitzgerald | 50 ug | 560.4 EUR | |
Flt3 ligand antibody | ||||
| 70R-31738 | Fitzgerald | 100 ug | 392.4 EUR | |
FAS ligand antibody | ||||
| 70R-31182 | Fitzgerald | 100 ug | 392.4 EUR | |
sRANK Ligand Antibody | ||||
| 3963-002mg | ProSci | 0.02 mg | 206.18 EUR | |
sRANK Ligand Antibody | ||||
| 3963-01mg | ProSci | 0.1 mg | 523.7 EUR | |
Here, we demonstrate that carboxylate ligands are the key element that enables the synthesis of these core-shell structures. Dynamic nuclear polarization surface-enhanced nuclear magnetic resonance spectroscopy (DNP SENS) in combination with density functional theory (DFT) structure calculations shows that the addition of the aluminum organometallic precursor forms a ligand-precursor complex that interacts with the NP surface. This ligand-precursor complex is the first step for the nucleation of the shell and enables its further growth.