Monovalent Ligands Research Articles

Self-assembled monovalent lipidated mannose ligand as a standalone nanoadjuvant

Subunit vaccines require an immunostimulant (adjuvant) and/or delivery system to induce immunity. However, currently, available adjuvants are either too dangerous in terms of side effects for human use (experimental adjuvants) or have limited efficacy and applicability. In this study, we examined the capacity of mannose-lipopeptide ligands to enhance the immunogenicity of a vaccine consisting of polyleucine(L15)-antigen conjugates anchored to liposomes. The clinically tested Group A Streptococcus (GAS) B-cell epitope, J8, combined with universal T helper PADRE (P) was used as the antigen. Six distinct mannose ligands were incorporated into neutral liposomes carrying L15PJ8. While induced antibody titers were relatively low, the ligand carrying mannose, glycine/lysine spacer, and two palmitic acids as liposomal membrane anchoring moieties (ligand 3), induced significantly higher IgG titers than non-mannosylated liposomes. The IgG titers were significantly enhanced when positively charged liposomes were employed. Importantly, the produced antibodies were able to kill GAS bacteria. Unexpectedly, the physical mixture of only ligand 3 and PJ8 produced self-assembled nanorods that induced antibody titers as high as those elicited by the lead liposomal formulation and antigen adjuvanted with the potent, but toxic, complete Freund’s adjuvant (CFA). Antibodies produced upon immunization with PJ8 + 3 were even more opsonic than those induced by CFA + PJ8. Importantly, in contrast to CFA, ligand 3 did not induce observable adverse reactions or excessive inflammatory responses. Thus, we demonstrated that a mannose ligand, alone, can serve as an effective vaccine nanoadjuvant.

Synthesis and unexpected binding of monofluorinated N,Nʹ-diacetylchitobiose and LacdiNAc to wheat germ agglutinin

Fluorination of carbohydrate ligands of lectins is a useful approach to examine their binding profile, improve their metabolic stability and lipophilicity, and convert them into 19F NMR-active probes. However, monofluorination of monovalent carbohydrate ligands often leads to a decreased or completely lost affinity. By chemical glycosylation, we synthesized the full series of methyl β-glycosides of N,N′-diacetylchitobiose (GlcNAcβ(1–4)GlcNAcβ1-OMe) and LacdiNAc (GalNAcβ(1–4)GlcNAcβ1-OMe) systematically monofluorinated at all hydroxyl positions. A competitive enzyme-linked lectin assay revealed that the fluorination at the 6′-position of chitobioside resulted in an unprecedented increase in affinity to wheat germ agglutinin (WGA) by one order of magnitude. For the first time, we have characterized the binding profile of a previously underexplored WGA ligand LacdiNAc. Surprisingly, 4′-fluoro-LacdiNAc bound WGA even stronger than unmodified LacdiNAc. These observations were interpreted using molecular dynamic calculations along with STD and transferred NOESY NMR techniques, which gave evidence for the strengthening of CH/π interactions after deoxyfluorination of the side chain of the non-reducing GlcNAc. These results highlight the potential of fluorinated glycomimetics as high-affinity ligands of lectins and 19F NMR-active probes.

Affinity enhancement of polo-like kinase 1 polo box domain-binding ligands by a bivalent approach using a covalent kinase-binding component.

The polo-like kinase 1 (Plk1) is an important cell cycle regulator that is recognized as a target molecule for development of anti-cancer agents. Plk1 consists of a catalytic kinase domain (KD) and a polo-box domain (PBD), which engages in protein-protein interactions (PPIs) essential to proper Plk1 function. Recently, we developed extremely high-affinity PBD-binding inhibitors based on a bivalent approach using the Plk1 KD-binding inhibitor, BI2536, and a PBD-binding peptide. Certain of the resulting bivalent constructs exhibited more than 100-fold Plk1 affinity enhancement relative to the best monovalent PBD-binding ligands. Herein, we report an extensive investigation of bivalent ligands that utilize the non-selective kinase inhibitor Wortmannin as a Plk1 KD-binding component. We found that bivalent ligands incorporating Wortmannin demonstrated affinity enhancements that could be similar to what we had obtained with BI2536 and that they could tightly bind to the protein. This suggests that these tight binding ligands might be useful for structural analysis of full-length Plk1.

Myosin light chain 6 (Myl6) interacts with kindlin-3 and is required to support integrin αIIbβ3 activation in platelets in mice

BackgroundKindlin-3 in platelets plays an essential role in supporting integrin αIIbβ3 activation, platelet spreading, aggregation, and clot retraction by binding to the integrin β3 cytoplasmic tail. However, the mechanism by which kindlin-3 mediates the crosstalk between integrin αIIbβ3 and myosin in platelets remains unknown. ObjectivesTo examine the role of myosin light chain 6 (Myl6) in supporting integrin αIIbβ3 activation in platelets. MethodsMyl6fl/flPF4-Cre mice with a deficiency of Myl6 in the megakaryocyte lineage were generated, and integrin αIIbβ3 activation in Myl6-deficient platelets was analyzed. ResultsWe identified a novel kindlin-3 binding protein, Myl6, an essential light chain of myosin in platelets. Myl6fl/flPF4-Cre mice exhibited significant macrothrombocytopenia resulting from defective proplatelet formation. In the absence of Myl6, integrin αIIbβ3 activation in platelets was significantly suppressed, and platelet aggregation was substantially impaired. Interestingly, the deficiency of Myl6 in platelets preferentially affected the binding of a multivalent ligand compared to a monovalent ligand to integrin αIIbβ3 upon activation, indicating that Myl6 may contribute to the avidity modulation of integrin αIIbβ3 by binding to kindlin-3. Furthermore, blood coagulation ability was impaired in Myl6fl/flPF4-Cre mice, and consistently, these mice exhibited defects in both hemostatic and thrombotic functions. ConclusionIn summary, these results suggest that Myl6, as a novel kindlin-3 binding partner, is required to support integrin αIIbβ3 activation in platelets, which plays an important role in both hemostasis and thrombosis.

Tetra‐ and Hexavalent Siglec‐8 Ligands Modulate Immune Cell Activation

AbstractCarbohydrate‐binding proteins are generally characterized by poor affinities for their natural glycan ligands, predominantly due to the shallow and solvent‐exposed binding sites. To overcome this drawback, nature has exploited multivalency to strengthen the binding by establishing multiple interactions simultaneously. The development of oligovalent structures frequently proved to be successful, not only for proteins with multiple binding sites, but also for proteins that possess a single recognition domain. Herein we present the syntheses of a number of oligovalent ligands for Siglec‐8, a monomeric I‐type lectin found on eosinophils and mast cells, alongside the thermodynamic characterization of their binding. While the enthalpic contribution of each binding epitope was within a narrow range to that of the monomeric ligand, the entropy penalty increased steadily with growing valency. Additionally, we observed a successful agonistic binding of the tetra‐ and hexavalent and, to an even larger extent, multivalent ligands to Siglec‐8 on immune cells and modulation of immune cell activation. Thus, triggering a biological effect is not restricted to multivalent ligands but could be induced by low oligovalent ligands as well, whereas a monovalent ligand, despite binding with similar affinity, showed an antagonistic effect.

Tetra- and Hexavalent Siglec-8 Ligands Modulate Immune Cell Activation.

Carbohydrate-binding proteins are generally characterized by poor affinities for their natural glycan ligands, predominantly due to the shallow and solvent-exposed binding sites. To overcome this drawback, nature has exploited multivalency to strengthen the binding by establishing multiple interactions simultaneously. The development of oligovalent structures frequently proved to be successful, not only for proteins with multiple binding sites, but also for proteins that possess a single recognition domain. Herein we present the syntheses of a number of oligovalent ligands for Siglec-8, a monomeric I-type lectin found on eosinophils and mast cells, alongside the thermodynamic characterization of their binding. While the enthalpic contribution of each binding epitope was within a narrow range to that of the monomeric ligand, the entropy penalty increased steadily with growing valency. Additionally, we observed a successful agonistic binding of the tetra- and hexavalent and, to an even larger extent, multivalent ligands to Siglec-8 on immune cells and modulation of immune cell activation. Thus, triggering a biological effect is not restricted to multivalent ligands but could be induced by low oligovalent ligands as well, whereas a monovalent ligand, despite binding with similar affinity, showed an antagonistic effect.

Tailoring multivalent nanomedicines for monkeypox

We have been through the largest monkeypox (Mpox) outbreak that has ever occurred globally. At present, the application of nanotechnology-based approaches to tackle Mpox has not been established. There are no US FDA-approved treatments for Mpox and it is plausible that, in forthcoming studies, researchers may investigate the use of multivalent nanomaterials to target the virus. In contrast to monovalent ligands, multi- and polyvalent ligands have strong affinity for the target molecules, thereby significantly facilitating the inhibition of viral attachment to host cells. Multivalent interactions are crucial in signal processing, adhesion, and recognition within biological systems. Based on the understanding of the development of multivalent nanomaterials (such as phage capsid nanoparticles, engineered bacteriophage T4 and self-assembled DNA nanobait) for SARS-CoV-2, influenza, and other viruses, this brief perspective gives insights into the development of next-generation multivalent nanomedicines targeting the entry-fusion complex of Mpox as a promising strategy for tackling emerging mutated strains.

LGR4 and LGR5 form distinct homodimers that only LGR4 complexes with RNF43/ZNRF3 to provide high affinity binding of R-spondin ligands

LGR4 and LGR5 are two homologous receptors that potentiate Wnt/β-catenin signaling in response to R-spondin (RSPO) ligands. The RSPO and LGR4 complex binds to and inhibits activities of two related E3 ubiquitin ligases, RNF43 and ZNRF3, and thus protects Wnt receptors from the E3 ligase-mediated degradation. The RSPO and LGR5 complex, however, does not interact with the E3 ligases, and the structural basis of this difference remained unknown. Here we examined the affinities of monovalent and bivalent RSPO ligands in binding to LGR4, RNF43/ZNRF3, and LGR5 in whole cells and found unique features among the receptors and E3 ligases. Monovalent RSPO2 furin domain had much lower affinity in binding to LGR4 or RNF43/ZNRF3 than the bivalent form. In contrast, monovalent and bivalent forms had nearly identical affinity in binding to LGR5. Co-expression of ZNRF3 with LGR4 led to much higher binding affinity of the monovalent form whereas co-expression of ZNRF3 with LGR5 had no effect on the affinity. These results suggest that LGR4 and RNF43/ZNRF3 form a 2:2 dimer that accommodates bivalent binding of RSPO whereas LGR5 forms a homodimer that does not. Structural models are proposed to illustrate how RSPOs bind to LGR4, RNF43/ZNRF3, and LGR5 in whole cells.

On the multivalency of large-ring cyclodextrins

The inclusion complexes of several large-ring cyclodextrins with a number of monovalent ligands (five or six adamantane molecules; CDn/mADA; n = 11, 12, 13, 14, 21, 26; m = 5 (for n = 11 to 14) or 6 (for n = 21, 26)) were examined with molecular dynamics simulations. The results demonstrate the high affinity of the LR-CDs to accommodate in their cavities this hydrophobic test particle. Most of the simulation time two guest molecules associate with the CD11 macrocycle. Two to four guest molecules are included in the cavities of CD12, CD13 and CD14 for the total of about 50% to 75% of the simulation time. Higher order associates of CD21 and CD26 with three to five adamantane substrates, comprise more than 40.0% of the snapshots taken from the simulation trajectories, and they still have remaining unoccupied binding sites that could accommodate even more adamantane molecules. Cluster analyses were performed with the k-mean and the bottom up agglomerative hierarchical methods. These LR-CDs, with theirs more than one docking sites are suitable candidates as multivalent receptors for specifically designed multivalent ligands.

A combined DFT and molecular docking study on novel tricarbonylrhenium(I) complexes bearing mono- and bivalent benzenesulfonamide scaffolds as human carbonic anhydrase IX and XII inhibitors

The aim of this study was to determine the reactivity and stability properties of a novel series of tricarbonylrhenium(I) complexes with 1,2,3-triazole-pyridine based on monovalent and bivalent benzenesulfonamide ligands as well as analyze their binding affinity within the active site of carbonic anhydrases IX and XII, using DFT and molecular docking. In the first setup, the DFT method was used to investigate the molecular geometries and vibrational frequencies of ligands and their Re(I) complexes. The basis set used was B3LYP/LanL2DZ-ECP/6-31G(d). The optimized geometric parameters (bond lengths and bond angles) and vibrational frequencies agree well with the experimental results. TD-DFT calculations were also performed to determine the influence of the methylene linker (-CH2-) on the bands found in the electronic spectra of these compounds. Global reactivity indices calculated from the energies of frontier molecular orbitals were used to assess their reactivity and stability properties (FMOs). Molecular electrostatic potential maps of the molecules were calculated to provide information about their chemical reactivity and to explain their intermolecular interactions. The computational data showed that bivalent ligands and their bivalent Re(I) complexes are more reactive than their monovalent counterparts. The second setup involves docking studies of the compounds within the active sites of the receptors (6QN2 for hCA IX and 1JD0 for hCA XII), which are performed using the Molegro Virtual Docker and AutoDock 4.2 programs, respectively. Our results indicate that bivalent ligands and their associated Re(I) complexes have a greater binding affinity than monovalent ligands and their associated Re(I) complexes. Compounds bis-L1 and bis-L2 exhibited the best affinity potential for hCA IX and hCA XII inhibition, making them the most promising candidates among those examined.

The Extracellular Electron Transport Pathway Reduces Copper for Sensing by the CopRS Two-Component System under Anaerobic Conditions in Listeria monocytogenes.

The renowned antimicrobial activity of copper stems in part from its ability to undergo redox cycling between Cu1+/2+ oxidation states. Bacteria counter copper toxicity with a network of sensors that often include two-component signaling systems to direct transcriptional responses. As in typical two-component systems, ligand binding by the extracellular domain of the membrane bound copper sensor component leads to phosphorylation and activation of the cognate response regulator transcription factor. In Listeria monocytogenes, the plasmid-borne CopRS two-component system upregulates both copper resistance and lipoprotein remodeling genes upon copper challenge, but the oxidation state of copper bound by CopS is unknown. Herein, we show CopS utilizes a triad of key residues (His-His-Phe) that are predicted to be at the dimerization interface and that are analogous with the Escherichia coli CusS copper sensor to specifically bind Cu1+/Ag1+ and activate CopR transcription. We demonstrate Cu2+ only induces CopRS if first reduced by electron transport systems, as strains lacking menaquinone carriers were unable to respond to Cu2+. The flavin-dependent extracellular electron transport system (EET) was the main mechanism for metal reduction, capable of either generating inducing ligand (Cu2+ to Cu1+) or removing it by precipitation (Ag1+ to Ag0). We show that EET flux is directly proportional to the rate of Cu2+ reduction and that since EET activity is low under oxygenated conditions when a competing respiratory chain is operating, CopRS signaling in turn is activated only under anaerobic conditions. EET metal reduction thus sensitizes cells to copper while providing resistance to silver under anaerobic growth. IMPORTANCE Two-component extracellular copper sensing from the periplasm of Gram-negative bacteria has been well studied, but copper detection at the cell surface of the Gram-positive L. monocytogenes is less understood. Collectively, our results show that EET is most active under anaerobic conditions and reduces Cu2+ and Ag1+ to, respectively, generate or remove the monovalent ligands that directly bind to CopS and lead to the induction of lipoprotein remodeling genes. This reducing activity regulates CopRS signaling and links the upregulation of copper resistance genes with increasing EET flux. Our studies provide insight into how a two-component copper sensing system is integrated into a model monoderm Firmicute to take cues from the electron transport chain activity.

Experimental validation of computerised models of clustering of platelet glycoprotein receptors that signal via tandem SH2 domain proteins.

The clustering of platelet glycoprotein receptors with cytosolic YxxL and YxxM motifs, including GPVI, CLEC-2 and PEAR1, triggers activation via phosphorylation of the conserved tyrosine residues and recruitment of the tandem SH2 (Src homology 2) domain effector proteins, Syk and PI 3-kinase. We have modelled the clustering of these receptors with monovalent, divalent and tetravalent soluble ligands and with transmembrane ligands based on the law of mass action using ordinary differential equations and agent-based modelling. The models were experimentally evaluated in platelets and transfected cell lines using monovalent and multivalent ligands, including novel nanobody-based divalent and tetravalent ligands, by fluorescence correlation spectroscopy. Ligand valency, receptor number, receptor dimerisation, receptor phosphorylation and a cytosolic tandem SH2 domain protein act in synergy to drive receptor clustering. Threshold concentrations of a CLEC-2-blocking antibody and Syk inhibitor act in synergy to block platelet aggregation. This offers a strategy for countering the effect of avidity of multivalent ligands and in limiting off-target effects.

DC-SIGN Binding to the Oligomannose-Type Glycans on the Surface Immunoglobulin Variable Region of Follicular Lymphoma Promotes Selective Adhesion to Microenvironmental VCAM-1

The selective acquisition of oligomannose-type glycans at the antigen-binding site of the surface immunoglobulin (sIg-Mann) is a tumor-specific post-translational modification of all follicular lymphomas (FL). Our immunogenetic and structural analyses have revealed that these oligomannoses at N-glycosylation sites are universally acquired and persist during the entire natural history of FL from the early stages throughout transformation into EZB lymphoma (Chiodin G, Blood 2021). If a FL cell loses these sites, which is rare, the progeny disappears unless a new glycosylation site is acquired (Odabashian M, Blood 2020). These data indicate that sIg-Mann is a fundamental functional requirement for the entire clonal population of all FLs. The low-affinity interaction of sIg-Mann with its specific ligand dendritic cell-specific intercellular adhesion molecule 3 grabbing non-integrin (DC-SIGN), expressed on interfollicular M2-macrophages and follicular dendritic cells (FDC) of FL (RadtkeA, BioRxiv, 2022), distinguishes from conventional high-affinity antigen:Ig protein interactions for promoting prolonged low-level growth and prosurvival signals via AKT and MYC and not endocytosis (Linley A, Blood 2015). However, the function of DC-SIGN:Ig-Mann remains to be further elucidated. In this study, we investigated the hypothesis that the specific engagement of DC-SIGN:Ig-Mann interaction functions to promote homing, while maintaining selective growth and survival signals. We found that DC-SIGN induced adhesion of sIg-Mann+ve lymphoma cells to VCAM-1 and inhibited migration towards SDF-1 in vitro. Blocking of DC-SIGN with an anti-DC-SIGN antibody specific to the carbohydrate-recognition domain completely abrogated DC-SIGN-induced adhesion, confirming that adhesion was mediated by the selective interaction with the oligomannose of sIg-Mann. Although intracellular signals were significantly lower than those by soluble anti-IgM F(ab)2 (here used to mimic the binding of cross-linking polyvalent antigen to Ig protein), the level of adhesion induced by DC-SIGN was similar to that induced by anti-IgM F(ab)2. Adhesion to VCAM-1 was observed at concentrations from 20 µg/ml down to 20 ng/ml, even when AKT and ERK phosphorylation was not detectable by immunoblotting. However, either proximal inhibition of the PI3K/AKT pathway or distal inhibition of ARP2/3, formin, Rac and Cdc42 for lamellipodium formation at the surface membrane, suppressed adhesion. This suggested that Ig-Mann-mediated adhesion required both low-level intracellular signals and membrane adaptation (Valle-Argos, Sci Rep 2021). Remarkably, unlike anti-IgM F(ab)2, adhesion was specific to VCAM-1 but not to other stromal elements including fibronectin (FN). Instead, using the sIg-Mann+ve (IGHV4-34+ve) WSU-FSCCL cells, DC-SIGN appeared to mimic the interaction of monovalent ligands, including Fab fragments to either the Ig constant (anti-IgM Fab) or Ig variable region (9G4 Fab, which recognizes an epitope in the framework region 1 of IGHV4-34). Like DC-SIGN, Fab fragments induced selective adhesion to VCAM-1 and low-level signals via AKT, but neither endocytosis nor adhesion to FN. These results identify an important functional role of the DC-SIGN:sIg-Mann in mediating a signal that is tuned at the right threshold to promote selective and, in the absence of Ig endocytosis, persistent adhesion to environmental VCAM-1, determining homing of the FL tumor cells in the lymph node. This tumor-specific antigen-independent low-affinity DC:SIGN-Ig-Mann interaction contrasts to conventional high-affinity antigen:Ig protein interaction, which is prevented in FL (Schneider D, Blood 2015) and would instead lead to endocytosis and death. Therapeutic interruption of the interaction of DC-SIGN+ve cells with sIg-Mann+ve FL cells would provide a new way to displace the tumor cells from their prosurvival microenvironment.

Phage display identification of nanomolar ligands for human NEDD4-WW3: Energetic and dynamic implications for the development of broad-spectrum antivirals

The recognition of PPxY viral Late domains by the third WW domain of the human HECT-E3 ubiquitin ligase NEDD4 (NEDD4-WW3) is essential for the budding of many viruses. Blocking these interactions is a promising strategy to develop broad-spectrum antivirals. As all WW domains, NEDD4-WW3 is a challenging therapeutic target due to the low binding affinity of its natural interactions, its high conformational plasticity, and its complex thermodynamic behavior. In this work, we set out to investigate whether high affinity can be achieved for monovalent ligands binding to the isolated NEDD4-WW3 domain. We show that a competitive phage-display set-up allows for the identification of high-affinity peptides showing inhibitory activity of viral budding. A detailed biophysical study combining calorimetry, nuclear magnetic resonance, and molecular dynamic simulations reveals that the improvement in binding affinity does not arise from the establishment of new interactions with the domain, but is associated to conformational restrictions imposed by a novel C-terminal -LFP motif in the ligand, unprecedented in the PPxY interactome. These results, which highlight the complexity of WW domain interactions, provide valuable insight into the key elements for high binding affinity, of interest to guide virtual screening campaigns for the identification of novel therapeutics targeting NEDD4-WW3 interactions.

Rigid Conjugated Diamine Templates for Stable Dion-Jacobson-Type Two-Dimensional Perovskites.

Hybrid organic-inorganic perovskites (HOIPs) have garnered widespread interest, yet stability remains a critical issue that limits their further application. Compared to their three-dimensional (3D) counterparts, two-dimensional (2D)-HOIPs exhibit improved stability. 2D-HOIPs are also appealing because their structural and optical properties can be tuned according to the choice of organic ligand, with monovalent or divalent ligands forming Ruddlesden-Popper (RP) or Dion-Jacobson (DJ)-type 2D perovskites, respectively. Unlike RP-type 2D perovskites, DJ-type 2D perovskites do not contain a van der Waals gap between the 2D layers, leading to improved stability. However, bifunctional organic ligands currently used to develop DJ-type 2D perovskites are limited to commercially available aliphatic and single-ring aromatic ammonium cations. Large conjugated organic ligands are in demand for their semiconducting properties and their potential to improve materials stability further. In this manuscript, we report the design and synthesis of a new set of larger conjugated diamine ligands and their incorporation into DJ-type 2D perovskites. Compared with analogous RP-type 2D perovskites, DJ 2D perovskites reported here show blue-shifted, narrower emissions and significantly improved stability. By changing the structure of rings (benzene vs thiophene) and substituents, we develop structure-property relationships, finding that fluorine substitution enhances crystallinity. Single-crystal structure analysis and density functional theory calculations indicate that these changes are due to strong electrostatic interactions between the organic templates and inorganic layers as well as the rigid backbone and strong π-π interaction between the organic ligands themselves. These results illustrate that targeted engineering of the diamine ligands can enhance the stability of DJ-type 2D perovskites.

Height, but not binding epitope, affects the potency of synthetic TCR agonists

Under physiological conditions, peptide-major histocompatibility complex (pMHC) molecules can trigger T cell receptors (TCRs) as monovalent ligands that are sparsely distributed on the plasma membrane of an antigen-presenting cell. TCRs can also be triggered by artificial clustering, such as with pMHC tetramers or antibodies; however, these strategies circumvent many of the natural ligand discrimination mechanisms of the T cell and can elicit nonphysiological signaling activity. We have recently introduced a synthetic TCR agonist composed of an anti-TCRβ Fab′ antibody fragment covalently bound to a DNA oligonucleotide, which serves as a membrane anchor. This Fab′-DNA ligand efficiently triggers TCR as a monomer when membrane associated and exhibits a potency and activation profile resembling agonist pMHC. In this report, we explore the geometric requirements for efficient TCR triggering and cellular activation by Fab′-DNA ligands. We find that T cells are insensitive to the ligand binding epitope on the TCR complex but that length of the DNA tether is important. Increasing, the intermembrane distance spanned by Fab′-DNA:TCR complexes decreases TCR triggering efficiency and T cell activation potency, consistent with the kinetic-segregation model of TCR triggering. These results establish design parameters for constructing synthetic TCR agonists that are able to activate polyclonal T cell populations, such as T cells from a human patient, in a similar manner as the native pMHC ligand.

Spectroscopic Identification of Disordered Molecular Cations in Defect Perovskite‐Like ALn(HCO2)(C2O4)1.5 (Ln=Tb‐Er) Phases

AbstractThis work reports a new series of ALn(HCO2)(C2O4)1.5 (A=[(CH3)2NH2]+ and Ln3+=Tb3+‐Er3+) compounds made solvothermally. These Cmce phases combine monovalent and divalent ligands, which enables a scarce combination of A+ and B3+ cations in a hybrid perovskite‐like compound. The ratio of ligands leads to ordered anion vacancies, which alternate with oxalate linkers along the c‐axis. The A‐site cations are disordered and cannot be identified crystallographically, likely a result of the larger pores of these frameworks compared to the recently reported AEr(HCO2)2(C2O4) phases. Neutron and infrared spectroscopy, supported by elemental composition, enables these cations to be identified as [(CH3)2NH2]+ molecules. Magnetic property measurements suggest these materials have weak antiferromagnetic interactions but remain paramagnetic to 1.8 K.

Progress on the surface ligand engineering of lead sulfide colloidal quantum dots

<p indent=0mm>Colloidal quantum dots (CQDs) are zero-dimensional semiconductor materials with solution-processable properties. These materials have attracted considerable attention in the research and development of new photodetectors, photovoltaic cells, light-emitting diodes, and chemical sensors. The large exciton Bohr radius and Debye length and the considerable quantum size effect make lead sulfide one of the typical hotspots in CQDs. Owing to the large specific surface area and abundant surface dangling bonds, the surface ligand of CQDs greatly influences their physical and chemical properties. Surface ligand engineering can be used to realize the functional design and performance improvement of quantum dot semiconductor devices. This article reviews the research progress in the surface ligand engineering of lead sulfide (PbS) CQDs, focusing on the influence of surface ligands on their conductive properties and chemical activity. To improve the surface passivation and carrier mobility, PbS CQDs are developed from short-chain organic ligands to inorganic ligands represented by metal chalcogenide complexes (MCC), especially by the introduction of monovalent halogen atomic ligands, through surface ligand engineering. We further introduce the liquid-phase ligand-exchange technology. Compared with film-level ligand exchange, liquid-phase ligand exchange favors complete ligand replacement and one-step deposition of quantum dot solids using a colloidal stable nanoparticle ink. With further detailed research, the air stability of PbS CQDs can be improved. This improvement will not only lay a solid foundation for the application of PbS CQDs in optoelectronic devices but also provide opportunities for the development of room-temperature chemical sensors. In the last part, we discuss the chemical activity of PbS CQDs and their application for gas sensing. CQDs are ideal gas-sensitive materials owing to their large surface area and abundant active sites for gas adsorption, and the surface states formed by gas adsorption considerably affect the physical and chemical properties of the CQDs. Meanwhile, the CQDs have excellent film-forming properties at room temperature. Hence, they can be coated on a silicon substrate by simple and controllable methods such as spin coating or spraying. In summary, the surface ligand engineering of CQDs is an important strategy to develop new semiconductor functional devices. The optoelectronic properties and chemical activity of PbS CQDs indicate sufficient scope for design and regulation with various types, components, and introduction methods of the surface ligand. Great breakthroughs have been made with regard to PbS CQDs in both stability research and low-cost mass production over the last decade. Despite various challenges, the basic research on PbS CQDs for photoelectric and chemical sensing is ongoing. To improve the design ideas and fabrication methods of CQD functional devices, it is necessary to use methods based on theoretical calculations and microcharacterization techniques to reveal the effect of surface ligands on CQDs. The understanding of surface science and device physics of CQDs will drive the utilization of the semiconductor quantum effect. In the future, great breakthroughs are expected for the use of PbS quantum dots in the fields of infrared imaging, spectral analysis, gas sensing, and biochemical sensing.

An fcu Th-MOF Constructed from In Situ Coupling of Monovalent Ligands

Synthetic efforts targeting highly symmetrical metal–organic frameworks (MOFs) have always been relentless, for the symmetry of a MOF’s pore environment and overall crystal structure are relevant to the MOF’s properties and behavior. Herein, we report a novel Th-based MOF constructed from assembling highly symmetrical Th-oxo clusters via in situ reductive coupling of nitroso groups on the cluster surface. Nitroso groups have long been known to dimerize in a reversible fashion. Putting them on the monovalent ligands that decorate the Th-oxo clusters can facilitate a downstream assembly process that link the said clusters in a controllable and predictable manner, preserving the overall symmetry in the MOF product. Moreover, the assembly can be made permanent by reducing the azodioxy moiety to azo, effectively locking the symmetrical MOF form. We believe this process of assembling pre-formed Th-oxo clusters helps the overall MOF adopt a highly symmetrical topology (face-centered cubic, fcu) resembling the well-known UiO series MOFs based on tetravalent Zr/Hf.

Identification and characterization of MAM03055A: A novel bivalent sigma-2 receptor/TMEM97 ligand with cytotoxic activity

Sigma-2 receptor/transmembrane protein 97 (TMEM97) is upregulated in cancer cells compared to normal cells. Traditional sigma-2 receptor agonists induce apoptosis and autophagy, making them of interest in cancer therapy. Recently, we reported a novel metabolically stimulative function of the sigma-2 receptor, showing increased 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction and stimulation of glycolytic hallmarks. 6-Substituted analogs of the canonical sigma-2 receptor antagonist, 6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one (SN79), produce both metabolically stimulative and cytotoxic effects. Here, we compare the activities of two related compounds: 6-amino-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one (CM571), the 6-amino derivative of SN79, which binds with high affinity to both sigma-1 and sigma-2 receptors, and 1,3-bis(3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)thiourea (MAM03055A), a homo-bivalent dimer of CM571. MAM03055A resulted from the degradation of 3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)-6-isothiocyanatobenzo[d]oxazol-2(3H)-one (CM572), the cytotoxic 6-isothiocyanato SN79 derivative. MAM03055A exhibited high affinity and strong preference for sigma-2 receptors (sigma-1 Ki = 3371 nM; sigma-2 receptor Ki = 55.9 nM). Functionally, MAM03055A treatment potently induced cell death in SK-N-SH neuroblastoma, MDA-MB-231 breast, and both SW48 and SW480 colorectal cancer cell lines, causing proapoptotic BH3 interacting-domain death agonist (BID) cleavage in SK-N-SH cells. Conversely, CM571 induced metabolic stimulation. CM571 bound reversibly to both receptors, while MAM03055A bound pseudo-irreversibly to sigma-2 receptors and caused residual cytotoxic activity after acute exposure and removal of the compound from the media. Interestingly, MAM03055A induced a time-dependent loss of sigma-2 receptor/TMEM97 protein from cells, whereas monomer CM571 had no effect on receptor levels. These results suggest that monovalent and bivalent sigma-2 receptor ligands in this series interact differently with the receptor, thus resulting in divergent effects.