Leveraging Metal Complexes for Microsecond Lifetime-Based Chloride Sensing.

Chloride is the most abundant anion in cells and plays many critical roles in maintaining cellular homeostasis. However, current chloride indicators are rare with inherent sensitivity in their emission properties, such as vulnerability to pH changes or short emission lifetimes. These limitations restrict their application in aqueous media and imaging.

Chloride Homeostasis Regulates cGAS-STING Signaling.

The cGAS-STING signaling pathway has emerged as a key mediator of inflammation. However, the roles of chloride homeostasis on this pathway are unclear. Here, we uncovered a correlation between chloride homeostasis and cGAS-STING signaling.

Author Correction: A pH-correctable, DNA-based fluorescent reporter for organellar calcium.

The originally published paper has been updated to include the following new reference, added as ref. 18: Albrecht, T., Zhao, Y.

A pH-correctable, DNA-based fluorescent reporter for organellar calcium.

It is extremely challenging to quantitate lumenal Ca in acidic Ca stores of the cell because all Ca indicators are pH sensitive, and Ca transport is coupled to pH in acidic organelles. We have developed a fluorescent DNA-based reporter, CalipHluor, that is targetable to specific organelles. By ratiometrically reporting lumenal pH and Ca simultaneously, CalipHluor functions as a pH-correctable Ca reporter.

A DNA nanomachine chemically resolves lysosomes in live cells.

Lysosomes are multifunctional, subcellular organelles with roles in plasma membrane repair, autophagy, pathogen degradation and nutrient sensing. Dysfunctional lysosomes underlie Alzheimer's disease, Parkinson's disease and rare lysosomal storage diseases, but their contributions to these pathophysiologies are unclear. Live imaging has revealed lysosome subpopulations with different physical characteristics including dynamics, morphology or cellular localization.

High lumenal chloride in the lysosome is critical for lysosome function.

Lysosomes are organelles responsible for the breakdown and recycling of cellular machinery. Dysfunctional lysosomes give rise to lysosomal storage disorders as well as common neurodegenerative diseases. Here, we use a DNA-based, fluorescent chloride reporter to measure lysosomal chloride in as well as murine and human cell culture models of lysosomal diseases.

Development of an Aptamer-Based Sensing Platform for Metal Ions, Proteins, and Small Molecules through Terminal Deoxynucleotidyl Transferase Induced G-Quadruplex Formation.

We report a label-free, structure-independent luminescent-sensing platform for metal ions, proteins, and small molecules utilizing an Ir(III) complex, terminal deoxynucleotidyl transferase (TdT), and a structure-folding aptamer. A novel G-quadruplex-selective Ir(III) complex was identified to detect the nascent G-quadruplex motifs with an enhanced luminescence response. Unlike most label-free DNA-based assays reported in the literature, this sensing platform does not require a specific secondary structure of aptamer, thus greatly simplifying DNA design.

An iridium(iii)-based irreversible protein-protein interaction inhibitor of BRD4 as a potent anticancer agent.

Bromodomain-containing protein 4 (BRD4) has recently emerged as an attractive epigenetic target for anticancer therapy. In this study, an iridium(iii) complex is reported as the first metal-based, irreversible inhibitor of BRD4. Complex is able to antagonize the BRD4-acetylated histone protein-protein interaction (PPI) , and to bind BRD4 and down-regulate c- oncogenic expression .

Label-free luminescence switch-on detection of hepatitis C virus NS3 helicase activity using a G-quadruplex-selective probe.

A series of luminescent Ir(iii) complexes were synthesised and evaluated for their ability to act as luminescent G-quadruplex-selective probes. The Ir(iii) complex , [Ir(phq)(phen)]PF (where phq = 2-phenylquinoline; phen = 1,10-phenanthroline), exhibited high luminescence in the presence of G-quadruplex DNA compared to dsDNA and ssDNA, and was employed to construct a label-free G-quadruplex-based assay for hepatitis C virus NS3 helicase activity in aqueous solution. Moreover, the application of the assay for screening potential helicase inhibitors was demonstrated.

A colorimetric chemosensor for Cu²⁺ ion detection based on an iridium(III) complex.

We report herein the synthesis and application of a series of novel cyclometalated iridium(III) complexes 1-3 bearing a rhodamine-linked NˆN ligand for the detection of Cu(2+) ions. Under the optimised conditions, the complexes exhibited high sensitivity and selectivity for Cu(2+) ions over a panel of other metal ions, and showed consistent performance in a pH value range of 6 to 8. Furthermore, the potential application of this system for the monitoring of Cu(2+) ions in tap water or natural river water samples was demonstrated.

A G-quadruplex-based, label-free, switch-on luminescent detection assay for Ag ions based on the exonuclease III-mediated digestion of C-Ag-C DNA.

We report herein the ability of exonuclease III to cleave C-Ag-C mismatched DNA, which was utilised for the construction of an exonuclease III-assisted, label-free, switch-on luminescent platform for Ag ions using a novel G-quadruplex-selective iridium(iii) complex.

Pharmacophore modeling for the identification of small-molecule inhibitors of TACE.

Tumor necrosis factor α-converting enzyme (TACE) plays a critical role in diverse physiological processes such as inflammation, hematopoiesis, and development. In this study, a pharmacophore model constructed from a training set of TACE inhibitors was used to screen an in-house database of organic compounds, from which compound 1 emerged as a top candidate. In a cell-free assay, compound 1 inhibited TACE enzymatic activity in a dose-dependent manner.

Discovery of deoxyvasicinone derivatives as inhibitors of NEDD8-activating enzyme.

NEDD8-activating enzyme (NAE) controls the specific degradation of proteins regulated by cullin-RING ubiquitin E3 ligases, and has been considered as an attractive molecular target for the development of drugs against cancer. A pharmacophore model constructed from a training set of deoxyvasicinone derivatives was used to screen 376 compounds from an analogue database. From the initial screening, the valine-linked deoxyvasicinone derivative 9 and the N-isopropyl-linked deoxyvasicinone derivative 10 emerged as the top scoring candidates.

Discovery of a small-molecule inhibitor of STAT3 by ligand-based pharmacophore screening.

STAT3 modulates the transcription of a wide variety of regulatory genes involved in cell proliferation, differentiation, migration, apoptosis, and other critical cellular functions. Constitutive activation of STAT3 has been detected in a wide spectrum of human malignancies. A pharmacophore model constructed from a training set of STAT3 inhibitors binding to the SH2 domain was used to screen an in-house database of compounds, from which azepine 1 emerged as a top candidate.

Antagonizing STAT3 dimerization with a rhodium(III) complex.

Kinetically inert metal complexes have arisen as promising alternatives to existing platinum and ruthenium chemotherapeutics. Reported herein, to our knowledge, is the first example of a substitutionally inert, Group 9 organometallic compound as a direct inhibitor of signal transducer and activator of transcription 3 (STAT3) dimerization. From a series of cyclometalated rhodium(III) and iridium(III) complexes, a rhodium(III) complex emerged as a potent inhibitor of STAT3 that targeted the SH2 domain and inhibited STAT3 phosphorylation and dimerization.

An oligonucleotide-based label-free luminescent switch-on probe for RNA detection utilizing a G-quadruplex-selective iridium(III) complex.

We report herein the synthesis and application of a novel G-quadruplex-selective luminescent iridium(iii) complex for the construction of an oligonucleotide-based, label-free, rapid and convenient luminescent RNA detection platform.

Antagonism of mTOR Activity by a Kinetically Inert Rhodium(III) Complex.

Kinetically inert Group 9 metal complexes have found emerging use as inhibitors of protein kinases or as modulators of protein-protein interactions. A series of cyclometalated rhodium(III) and iridium(III) complexes was investigated as inhibitors of mammalian target of rapamycin (mTOR) activity. Cell-free and cell-based experiments revealed rhodium(III) complex 1 to be a potent mTOR inhibitor (IC =0.

Label-free luminescence switch-on detection of T4 polynucleotide kinase activity using a G-quadruplex-selective probe.

A label-free, oligonucleotide-based, switch-on luminescence detection method for T4 polynucleotide kinase activity has been developed using a novel G-quadruplex-selective luminescent Ir(iii) complex probe. The application of the assay for screening potential T4 PNK inhibitors is also demonstrated. To our knowledge, this is the first metal-based assay for PNK activity.

Label-free luminescent switch-on detection of endonuclease IV activity using a G-quadruplex-selective iridium(III) complex.

We report herein the synthesis and application of a novel G-quadruplex-selective luminescent iridium(III) complex [Ir(ppy)2(bcp)](+) (where ppy = 2-phenylpyridine and bcp = 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline) for the sensitive detection of apurinic/apyrimidinic (AP) endonuclease activity. Using endonuclease IV (Endo IV) as a model enzyme, a duplex DNA substrate containing a G-quadruplex-forming sequence is cleaved by Endo IV at the abasic site. This releases the G-quadruplex sequence, which folds into a G-quadruplex and is recognised by the G-quadruplex-selective iridium(III) complex with an enhanced luminescence response.

A label-free luminescent switch-on assay for ATP using a G-quadruplex-selective iridium(III) complex.

We report herein the G-quadruplex-selective property of a luminescent cyclometallated iridium(III) complex for the detection of adenosine-5'-triphosphate (ATP) in aqueous solution. The ATP-binding aptamer was employed as the ATP recognition unit, while the iridium(III) complex was used to monitor the formation of the G-quadruplex structure induced by ATP. The sensitivity and fold enhancement of the assay were higher than those of the previously reported assay using the organic dye crystal violet as a fluorescent probe.

Bioactive luminescent transition-metal complexes for biomedical applications.

The serendipitous discovery of the anticancer drug cisplatin cemented medicinal inorganic chemistry as an independent discipline in the 1960s. Luminescent metal complexes have subsequently been widely applied for sensing, bio-imaging, and in organic light-emitting diode applications. Transition-metal complexes possess a variety of advantages that make them suitable as therapeutics and as luminescent probes for biomolecules.