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.

Proteomic and phosphoproteomic analyses of Jurkat T-cell treated with 2'3' cGAMP reveals various signaling axes impacted by cyclic dinucleotides.

Cyclic dinucleotides (CDNs), such as 2'3'-cGAMP, bind to STING to trigger the production of cytokines and interferons, mainly via activation of TBK1. STING activation by CDN also leads to the release and activation of Nuclear Factor Kappa-light-chain-enhancer of activated B cells (NF-κB) via the phosphorylation of Inhibitor of NF-κB (IκB)-alpha (IκBα) by IκB Kinase (IKK). Beyond the canonical TBK1 or IKK phosphorylations, little is known about how CDNs broadly affect the phosphoproteome and/or other signaling axes.

c-di-GMP Induces COX-2 Expression in Macrophages in a STING-Independent Manner.

Many pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS) and lipoteichoic acid, are potent immunostimulatory molecules and promote the expression of cyclooxygenase 2 (COX-2). While the production of COX-2, and ultimately prostaglandin E, could be protective, persistent induction of COX-2 leads to inflamed environments that can result in septic shock and death. Bacterial derived cyclic dinucleotides (CDNs), c-di-GMP and c-di-AMP, are also PAMPs and have been shown to produce inflamed environments via the production of pro-inflammatory cytokines such as type I interferons.

HSD1787, a Tetrahydro-3-Pyrazolo[4,3-]Quinoline Compound Synthesized via Povarov Reaction, Potently Inhibits Proliferation of Cancer Cell Lines at Nanomolar Concentrations.

Multicomponent reaction (MCR) is often used to rapidly assemble complex compounds for drug screening. Povarov MCR has been used to prepare a new library containing tetrahydro-3-pyrazolo[4,3-]quinoline core and the library tested against MDA-MB-231 (a triple-negative breast cancer, TNBC, cell line). A few of the tetrahydro-3-pyrazolo[4,3-]quinoline-containing compounds, bearing 3-aminoindazolyl group, potently inhibited MDA-MB-231.

Interrupting cyclic dinucleotide-cGAS-STING axis with small molecules.

The cyclic dinucleotide-cGAS-STING axis plays important roles in host immunity. Activation of this signaling pathway, cytosolic sensing of bacterial-derived c-di-GMP/c-di-AMP or host-derived cGAMP, leads to the production of inflammatory interferons and cytokines that help resolve infection. Small molecule activators of the cGAS-STING axis have the potential to augment immune response against various pathogens or cancer.

Global Proteomic Analyses of STING-Positive and -Negative Macrophages Reveal STING and Non-STING Differentially Regulated Cellular and Molecular Pathways.

Purpose: Cyclic guanosine monophosphate-adenosine monophosphate and other bacterial-derived cyclic di-guanosine monophosphate or cyclic di-adenosine monophosphate trigger innate immune responses through binding to stimulator of interferon genes (STING). Thus in chronic infection, such as in periodontitis, immune cells can be exposed to bacterial DNA and/or cyclic dinucleotides, potentially activating STING to cause inflammation. Thus far the cyclic GMP-AMP synthase-STING- TANK-binding kinase 1 pathway has been well characterized but a global perspective of how the presence or lack of STING affect the proteome is lacking.

ENPP1, an Old Enzyme with New Functions, and Small Molecule Inhibitors-A STING in the Tale of ENPP1.

Ectonucleotide pyrophosphatase/phosphodiesterase I (ENPP1) was identified several decades ago as a type II transmembrane glycoprotein with nucleotide pyrophosphatase and phosphodiesterase enzymatic activities, critical for purinergic signaling. Recently, ENPP1 has emerged as a critical phosphodiesterase that degrades the stimulator of interferon genes (STING) ligand, cyclic GMP-AMP (cGAMP). cGAMP or analogs thereof have emerged as potent immunostimulatory agents, which have potential applications in immunotherapy.

Inhibitors of Intracellular Gram-Positive Bacterial Growth Synthesized via Povarov-Doebner Reactions.

can survive both inside and outside of phagocytic and nonphagocytic host cells. Once in the intracellular milieu, most antibiotics have reduced ability to kill , thus resulting in relapse of infection. Consequently, there is a need for antibacterial agents that can accumulate to lethal concentrations within host cells to clear intracellular infections.

Identification of nicotinamide aminonaphthyridine compounds as potent RET kinase inhibitors and antitumor activities against RET rearranged lung adenocarcinoma.

RET rearrangement is a recently identified oncogenic mutation in lung adenocarcinoma (LADC) that accounts for approximately 2% of all NSCLCs. More than six fusion partners have been identified in NSCLC, such as KIF5B, CCDC6, NCOA4, TRIM33, CLIP1 and ERC1. Many RET inhibitors have been reported and some have progressed to the clinic.

Amino alkynylisoquinoline and alkynylnaphthyridine compounds potently inhibit acute myeloid leukemia proliferation in mice.

Background: Acute myeloid leukemia (AML) remains one of the most lethal, rarely cured cancers, despite decades of active development of AML therapeutics. Currently, the 5-year survival of AML patients is about 30% and for elderly patients, the rate drops to <10%. About 30% of AML patients harbor an activating mutation in the tyrosine kinase domain (TKD) of Fms-Like Tyrosine kinase 3 (FLT3) or a FLT3 internal tandem duplication (FLT3-ITD).

Discriminating cyclic from linear nucleotides - CRISPR/Cas-related cyclic hexaadenosine monophosphate as a case study.

Nucleic acids exist in biological systems as linear and cyclic forms and in most cases the biology of the cyclic form is different from the linear form of exactly the same sequence. Case examples are cyclic nucleotides, second messengers in both prokaryotes and eukaryotes whereby the cyclic forms account for their interesting biological profiles and the actions of the cyclic nucleotides are terminated upon phosphodiesterase hydrolysis into linear forms. For mono and dinucleotides, it has been shown that vast conformational changes that accompany the hydrolysis of the cyclized form allow for discrimination between the cyclized and linear forms.

Suramin potently inhibits cGAMP synthase, cGAS, in THP1 cells to modulate IFN-β levels.

Aim: Persistent activation of STING pathway is the basis for several autoimmune diseases. STING is activated by cGAMP, which is produced by cGAS in the presence of DNA. Results/methodology: HPLC-based medium throughput screening for inhibitors of cGAS identified suramin as a potent inhibitor.

Conjugating a groove-binding motif to an Ir(iii) complex for the enhancement of G-quadruplex probe behavior.

In this study, the reported G-quadruplex groove binder benzo[,]isoquinoline was linked to a cyclometallated Ir(iii) complex to generate a highly selective DNA probe that retains the favorable photophysical properties of the parent complex. The linked complex showed advantages of both parent complex and groove binder . Similar to , the conjugated complex exhibits a superior affinity and selectivity for G-quadruplex DNA over other conformations of DNA or proteins, with the fold enhancement ratio obviously improved compared with parent complex .

A luminescent G-quadruplex-selective iridium(iii) complex for the label-free detection of lysozyme.

A novel Ir(iii) complex 1 displays high selectivity for the G-quadruplex, and was used to establish a label-free G-quadruplex-based detection platform for lysozyme in buffer. In this study, we employed a special feature of most G-quadruplex probes that they do not respond towards the TBA G-quadruplex. A duplex DNA with a TBA G-quadruplex tail was designed for the detection of lysozyme.

Identification of an Iridium(III)-Based Inhibitor of Tumor Necrosis Factor-α.

The novel iridium(III) complex 1 was verified as a potent inhibitor of the TNF-α-TNFR protein-protein interaction in vitro and in cellulo. The iridium(III) center plays a critical role in organizing the structure of the bioactive metal complex, as the isolated ligands were found to be completely inactive. Both iridium enantiomers inhibited TNF-α-induced NF-κB activity and TNF-α-TNFR binding.

A novel dinuclear iridium(III) complex as a G-quadruplex-selective probe for the luminescent switch-on detection of transcription factor HIF-1α.

A novel dinuclear Ir(III) complex 5 was discovered to be specific to G-quadruplex DNA, and was utilized in a label-free G-quadruplex-based detection platform for transcription factor activity. The principle of this assay was demonstrated by using HIF-1α as a model protein. Moreover, this HIF-1α detection assay exhibited potential use for biological sample analysis.

A long lifetime luminescent iridium(III) complex chemosensor for the selective switch-on detection of Al(3+) ions.

A novel luminescent cyclometalated iridium(III) complex was synthesized and employed as a chemosensor for the detection of Al(3+) ions. Compared with common organic chemosensors, displays a larger Stokes shift and a long lifetime luminescence that allow to detect Al(3+) ions in fluorescent dye spiked strong fluorescence media and potentially be used in strongly autofluorescent biological samples.

A long lifetime switch-on iridium(III) chemosensor for the visualization of cysteine in live zebrafish.

A long lifetime iridium(III) complex chemosensor 1 for cysteine detection has been synthesized. The luminescence signal of 1 could be recognized in strongly fluorescent media through time-resolved emission spectroscopy (TRES). The detection of cysteine in a living zebrafish was demonstrated.

Rhodium complexes as therapeutic agents.

The landscape of inorganic medicinal chemistry has been dominated by the investigation of platinum, and to a lesser extent ruthenium, complexes over the past few decades. Recently, complexes based on other metal centers such as rhodium have attracted attention due to their tunable chemical and biological properties as well as distinct mechanisms of action. This perspective highlights recent examples of rhodium complexes that show diverse biological activities against various targets, including enzymes and protein-protein interactions.

Development of an Iridium(III) Complex as a G-Quadruplex Probe and Its Application for the G-Quadruplex-Based Luminescent Detection of Picomolar Insulin.

In this study, an unreported Ir(III) complex 1 was identified by screening as a versatile G-quadruplex probe. It exhibited highly selective response for different G-quadruplex DNA over double strand, single strand and triplex DNA. Compared with the organic G-quadruplex probe thioflavin T, complex 1 displays a longer lifetime, a larger Stokes shift, comparable G-quadruplex/ssDNA enhancement ratios, and higher G-quadruplex/triplex DNA enhancement ratios.

Inhibition of Beta-Amyloid Fibrillation by Luminescent Iridium(III) Complex Probes.

We report herein the application of kinetically inert luminescent iridium(III) complexes as dual inhibitors and probes of beta-amyloid fibrillogenesis. These iridium(III) complexes inhibited Aβ1-40 peptide aggregation in vitro, and protected against Aβ-induced cytotoxicity in neuronal cells. Furthermore, the complexes differentiated between the aggregated and unaggregated forms of Aβ1-40 peptide on the basis of their emission response.

Identification of an iridium(III) complex with anti-bacterial and anti-cancer activity.

Group 9 transition metal complexes have been widely explored as therapeutic agents due to their unique geometry, their propensity to undergo ligand exchanges with biomolecules and their diverse steric and electronic properties. These metal complexes can offer distinct modes of action in living organisms compared to carbon-based molecules. In this study, we investigated the antimicrobial and anti-proliferative abilities of a series of cyclometallated iridium(III) complexes.

A Luminescent Cocaine Detection Platform Using a Split G-Quadruplex-Selective Iridium(III) Complex and a Three-Way DNA Junction Architecture.

In this study, a series of 10 in-house cyclometalated iridium(III) complexes bearing different auxiliary ligands were tested for their selectivity toward split G-quadruplex in order to construct a label-free switch-on cocaine detection platform employing a three-way junction architecture and a G-quadruplex motif as a signal output unit. Through two rounds of screening, we discovered that the iridium(III) complex 7 exhibited excellent selectivity toward the intermolecular G-quadruplex motif. A detection limit as low as 30 nM for cocaine can be achieved by this sensing approach with a linear relationship between luminescence intensity and cocaine concentration established from 30 to 300 nM.

Recent Developments in G-Quadruplex Probes.

Accumulating evidence has linked G-quadruplex structures to a number of biological processes in vivo, including DNA replication, transcription, and genomic maintenance. However, the precise function and mechanism of G-quadruplex formation in mammalian cells remains poorly defined. Therefore, the development of small-molecule G-quadruplex probes has attracted significant attention in recent years.

G-quadruplex-based logic gates for Hg and Ag ions employing a luminescent iridium(iii) complex and extension of metal-mediated base pairs by polymerase.

We report herein the synthesis of a series of cyclometallated iridium(iii) complexes as luminescent G-quadruplex-selective probes, which were used to construct AND, OR and INHIBIT logic gates for the detection of Hg and Ag ions. To our knowledge, this is the first time that the C-Ag-T mismatched base pair has been used for the construction of luminescent assays or logic gates.