Reversible Ligand Research Articles

Identification and Evaluation of Reversible Covalent Binders to Cys55 of Bfl-1 from a DNA-Encoded Chemical Library Screen.

Bfl-1 is overexpressed in both hematological and solid tumors; therefore, inhibitors of Bfl-1 are highly desirable. A DNA-encoded chemical library (DEL) screen against Bfl-1 identified the first known reversible covalent small-molecule ligand for Bfl-1. The binding was validated through biophysical and biochemical techniques, which confirmed the reversible covalent mechanism of action and pointed to binding through Cys55. This represented the first identification of a cyano-acrylamide reversible covalent compound from a DEL screen and highlights further opportunities for covalent drug discovery through DEL screening. A 10-fold improvement in potency was achieved through a systematic SAR exploration of the hit. The more potent analogue compound 13 was successfully cocrystallized in Bfl-1, revealing the binding mode and providing further evidence of a covalent interaction with Cys55.

Reversible Ligand Detachment from CdSe Quantum Dots Following Photoexcitation.

The nanocrystal-ligand boundaries of colloidal quantum dots (QDs) mediate charge and energy transfer processes that underpin photochemical and photocatalytic transformations at their surfaces. We used time-resolved infrared spectroscopy combined with transient electronic spectroscopy to probe vibrational modes of the carboxylate anchoring groups of stearate ligands attached to cadmium selenide (CdSe) QDs that were optically excited in solid nanocrystal films. The vibrational frequencies of surface-bonded carboxylate groups revealed their interactions with surface-localized holes in the excited states of the QDs. We also observed transient and reversible photoinduced ligand detachment from CdSe nanocrystals within their excited state lifetime. By probing both surface charge distributions and ligand dynamics on QDs in their excited states, we open a pathway to explore how the nanocrystal-ligand boundary can be understood and controlled for the design of QD architectures that most effectively drive charge transfer processes in solar energy harvesting and photoredox catalysis applications.

Reversible Aptamer Staining, Sorting, and Cleaning of Cells (Clean FACS) with Antidote Oligonucleotide or Nuclease Yields Fully Responsive Cells.

The ability to reverse the binding of aptamers to their target proteins has received considerable attention for developing controllable therapeutic agents. Recently, use of aptamers as reversible cell-sorting ligands has also sparked interest. Antibodies are currently utilized for isolating cells expressing a particular cell surface receptor. The inability to remove antibodies from isolated cells following sorting greatly limits their utility for many applications. Previously, we described how a particular aptamer-antidote oligonucleotide pair can isolate cells and clean them. Here, we demonstrate that this approach is generalizable; aptamers can simultaneously recognize more than one cell type during fluorescent activated cell sorting (FACS). Moreover, we describe a novel approach to reverse aptamer binding following cell sorting using a nuclease. This alternative strategy represents a cleaning approach that does not require the generation of antidote oligonucleotides for each aptamer and will greatly reduce the cost and expand the utility of Clean FACS.

DNA-functionalized hyaluronic acid bioink in cartilage engineering: a perspective

Degenerative osteoarthritis, a common sequela of articular cartilage defect, significantly impacts the quality of life of millions of individuals worldwide. Three-dimensional (3D) bioprinting has emerged as an advanced tissue engineering strategy, offering precise spatial arrangements of cells, hydrogels, and bioactive cues. Hyaluronic acid (HA) is a crucial component of bioink designed for fabricating cartilage tissue. However, creating a bioink that closely mimics the cartilaginous extracellular matrix (ECM) still remains a challenge. HA hydrogels have limitations in recapitulating tunable mechanical properties, stimuli responsiveness, and flexibility in ligands’ adhesion akin to those of native tissues. In recent years, DNA has emerged as a smart biomaterial that endows hydrogels with tunable properties and allows for precise structural customization of the hydrogels due to its unique programmability. Integrating reversible DNA linkages, reconfigurable DNA architectures, DNA plasmid, and targeted DNA aptamers into HA hydrogels allows them to respond to the extracellular environment and express desired molecules, making them ideal artificial ECMs for 3D bioprinting of cartilage tissue. This review targets this challenge by highlighting the characteristics of DNA moieties designed as reversible crosslinkers, responsive units, and adhesion ligands to functionalize HA hydrogels. Furthermore, we offer perspectives on how DNA-functionalized HA hydrogels can be harnessed to create dynamic and biomimetic bioink capable of recapitulating the more complex functions required for cartilage tissue engineering.

Ligand redox controlled amine dehydrogenation and imine hemilability in singlet diradical azo-aromatic Ni(II) complexes: characterization of the electron transfer series of azo-imine complexes of Ni(II).

Herein, using azo-amine (H2L) and azo-imine (L1-3) ligands, singlet diradical Ni(II) complexes [1] and [2] were synthesized from Ni(0)(COD)2 in THF. In separate reactions, homoleptic NiII complexes, [3a]2+-[3c]2+, were synthesized from [NiII(H2O)6](ClO4)2 and L1-3, respectively. All these complexes were characterized thoroughly. The X-ray structures of [1] and [2] showed that the amine side arm in [1] and the imine side arm in [2] are de-coordinated. The dN-N lengths in these two complexes were found to be ∼1.32 Å, which corresponds to the one-electron reduced azo-bond length. These complexes, [1] and [2], showed 1H NMR signals characteristic of diamagnetic compounds. These studies, along with DFT calculations, indicated that the unpaired spins on ligands coupled antiferromagnetically with the two unpaired spins on NiII to result in s = 0 ground states. Complex [1] showed ligand-based redox-induced dehydrogenation of the distal amine side arm to result in L1. Complexes [3a]2+-[3c]2+ have dN-N lengths of ∼1.27 Å and dC-N lengths of ∼1.28 Å. In cyclic voltammetry, complex [3a]2+ showed four well-resolved reversible reductive waves at 0.5 V to -1.6 V in dichloromethane. The first two waves became irreversible when they were measured in acetonitrile solution. The electron transfer series of [3a]2+ was further characterized by spectro-electrochemistry, EPR, and DFT calculations. These showed that all the reductions were associated with the ligand. It was further probed by redox events in complexes [3b]2+ and [3c]2+. While the electron donor -OMe group on the phenyl ring of the azo moiety in [3b]2+ showed a prominent cathodic shift of the potentials, the -F substitution on the phenyl group on the imine side arm of [3c]2+ has almost no effect. It has to be noted here that the oxidation of [2] by two electrons returns it back to complex [3a]2+. Reduction of [3a]2+ by two electrons also resulted in complex [2], indicating reversible ligand redox-induced hemilability of the imine moiety between [3a]2+ and [2]. Moreover, characterization of the electron transfer series of [3a]2+ and [2] has shown superior redox non-innocent behaviour and coordination ability of the azo-pyridine moiety in nickel(II) complexes over the imino-pyridine moiety of the ligand.

MARCKS Effector Domain, a reversible lipid ligand, illuminates late stages of membrane fusion.

Yeast vacuolar HOPS tethers membranes, catalyzes trans-SNARE assembly between R- and Q-SNAREs, and shepherds SNAREs past early inhibition by Sec17. After partial SNARE zippering, fusion is driven slowly by either completion of SNARE zippering or by Sec17/Sec18, but rapid fusion needs zippering and Sec17/Sec18. Using reconstituted-vacuolar fusion, we find that MARCKS Effector Domain (MED) peptide, a lipid ligand, blocks fusion reversibly at a late reaction stage. The MED fusion blockade is overcome by either salt extraction, inactivation with the MED ligand calmodulin, or addition of Sec17/Sec18. During incubation with MED, SNAREs assemble stable complexes in trans and fusion becomes resistant to antibody to the Qa SNARE. When Q-SNAREs are preassembled, a synthetic tether can replace HOPS for fusion. With a synthetic tether, fusion needs both complete SNARE zippering and Sec17/Sec18 to overcome a MED block. In contrast, when SNARE domains are only two-third zippered, only HOPS will support Sec17/Sec18 driven fusion without needing complete zippering. HOPS thus remains engaged with SNAREs during zippering. MED facilitates the study of distinct fusion stages: tethering, initial trans-SNARE assembly and its sensitivity to Sec17, SNARE zippering, Sec17/Sec18 engagement, and lipid and lumenal mixing.

Reversible ligand exchange of triphenylphosphine with thiols on gold nanoparticles for Janus modification and catalyst recycling

Separation and regeneration of ultrafine catalysts in reaction system still remain challenging. In this study, we demonstrate a simple route to recycle gold nanoparticle (Au NP) catalysts by alternating surface wettability. Hydrophilic Au NPs protected with 3-mercapto-1,2-propanediol (MPD) were applied to catalyze the reduction of 4-nitrophenol (4-NP) using sodium borohydride as reductant, and were then separated from the suspension by interfacial ligand exchange with a toluene solution containing triphenylphosphine (TPP), led to amphiphilic Janus Au NPs with both MPD and TPP ligands at the toluene-water interface. The catalyst was regenerated by a reversible ligand exchange with a MPD aqueous solution. Experiments show that interfacial ligand exchange between phosphines and thiols on gold surface is reversible, although the forward and backward rates are different. As a result, the Au NP catalyst capped with MPD exhibited an excellent catalytic activity with an apparent rate constant (k) of 2.79 min−1, and the performance could be maintained for more than 10 regeneration cycles. The facile conversion between hydrophilic and amphiphilic Janus Au NPs provides a new pathway to explore monophasic and multiphasic reactions with convenient catalyst separation and regeneration.

Reversible Metal and Ligand Redox Chemistry in Two-Dimensional Iron-Organic Framework for Sustainable Lithium-Ion Batteries.

Metal-organic frameworks (MOFs) are emerging as attractive electrode materials for lithium-ion batteries, owing to their fascinating features of sustainable resources, tunable chemical components, flexible molecular skeletons, and renewability. However, they are faced with a limited number of redox-active sites and unstable molecular frameworks during electrochemical processes. Herein, we design a novel two-dimensional (2D) iron(III)-tetraamino-benzoquinone (Fe-TABQ) with dual redox centers of Fe cations and TABQ ligands for high-capacity and stable lithium storage. It is constructed of square-planar Fe-N2O2 linkages and phenylenediamine building blocks, between which the Fe-TABQ chains are connected by multiple hydrogen bonds, and then featured as an extended π-d-conjugated 2D structure. The redox chemistry of both Fe3+ cations and TABQ anions is revealed to render its remarkable specific capacity of 251.1 mAh g-1. Benefiting from the intrinsic robust Fe-N(O) bonds and reinforced Li-N(O) bonds during cycling, Fe-TABQ delivers high capacity retentions over 95% after 200 cycles at various current densities. This work will enlighten more investigations for the molecular designs of advanced MOF-based electrode materials.

Dopamine D2/3 Receptor Availabilities in Striatal and Extrastriatal Regions of the Adult Human Brain: Comparison of Four Methods of Analysis.

Values of binding potentials (BPND) of dopamine D2/3 receptors differ in different regions of the brain, but we do not know with certainty how much of this difference is due either to different receptor numbers, or to different affinities of tracers to the receptors, or to both. We tested the claim that both striatal and extrastriatal dopamine D2/3 receptor availabilities vary with age in vivo in humans by determining the values of BPND of the specific radioligand [11C]raclopride. We determined values of BPND in striatal and extrastriatal volumes-of-interest (VOI) with the same specific receptor radioligand. We estimated values of BPND in individual voxels of brains of healthy volunteers in vivo, and we obtained regional averages of VOI by dynamic positron emission tomography (PET). We calculated average values of BPND in caudate nucleus and putamen of striatum, and in frontal, occipital, parietal, and temporal cortices of the forebrain, by means of four methods, including the ERLiBiRD (Estimation of Reversible Ligand Binding and Receptor Density) method, the tissue reference methods of Logan and Logan-Ichise, respectively, and the SRTM (Simplified Reference Tissue Method). Voxelwise generation of parametric maps of values of BPND used the multi-linear regression version of SRTM. Age-dependent changes of the binding potential presented with an inverted U-shape with peak binding potentials reached between the ages of 20 and 30. The estimates of BPND declined significantly with age after the peak in both striatal and extrastriatal regions, as determined by all four methods, with the greatest decline observed in posterior (occipital and parietal) cortices (14% per decade) and the lowest decline in caudate nucleus (3% per decade). The sites of the greatest declines are of particular interest because of the clinical implications.

Organic ligand complementary passivation to Colloidal-quantum-dot surface enables efficient infrared solar cells

Lead sulfide colloidal quantum dot (PbS CQD) solar cells present great potential in infrared (IR) conversion due to high IR absorption coefficient and solution processability. The large-size IR QDs introduce specific nonpolar (100) facets that undisplay in small-size CQDs. The neutrality of (100) facets and reversible ligand exchange process are crucial challenges for IR QD surface passivation. Here, organic halide salt phenethylammonium iodide/bromine (PEAX, X = I/Br) additive ligands are adopted to cooperate with traditional lead halides for QD surface passivation especially for (100) neutral facets. Both nuclear magnetic resonance (NMR) and density functional theory (DFT) simulation reveal that the organic ligand PEAX can bind on PbS QD planes to enhance passivation without compromising transport property. Further device related photophysical studies confirm the suppressed bulk and interface defect concentration. The optimal PEABr based solar cells possess a power conversion efficiency (PCE) of 12.28 % under solar AM1.5G (certified value of 11.98 %). The crystalline Si filtered efficiency reaches 1.42 %. Both efficiencies are the record values for such absorption range QD (excitonic peak ∼1.3 μm) solar cells. Moreover, the supplementary PEAX ligand suppress the migration of halogen ions and elevate device stability.

Platelet Count Threshold Associated with Bleeding in Adult Patients with Immune Thrombocytopenia Treated with Antiplatelet Drugs. Results from the Carmen-France Registry

Introduction: In 2019, international guidelines for the management of immune thrombocytopenia (ITP) stated that ITP treatment is rarely indicated in case of platelet count >20 x109/L. The threshold associated with significant bleeding in ITP patients treated with antiplatelet agents is unknown, and 2019 American society of hematology guidelines for ITP management stressed the need for studies to determine it. This was the aim of this study. Methods: The source of data was the CARMEN-France registry, a prospective, real-world registry of incident ITP adults in the French Midi-Pyrénées region since June 2013, implemented in other centers of the French Autoimmune cytopenia referral center network since 2016. Inclusion criteria were adult patients (aged ≥18 years) newly diagnosed with ITP (platelet count <100 x 109/L and exclusion of other causes of thrombocytopenia). We designed a transversal study to correlate the platelet count to bleeding at ITP diagnosis, before any ITP treatment. Study population consisted in the patients included in the registry up to November 2021 and treated with antiplatelet agents at the time of ITP diagnosis, without concomitant exposure to anticoagulant. We quantified the percentages of patients with overall bleeding, cutaneous bleeding, non-serious mucosal bleeding and serious bleeding (defined by intracranial bleeding, gastro-intestinal bleeding or gross hematuria with anemia) by categories of platelet count (by 109/L up to 50 x 109/L then ≥50 x 109/L). Analyses were conducted by subgroups of antiplatelet agents due to suspected differences in pharmacological effect in patients with ITP who have a high platelet turn over: patients treated with clopidogrel and ticagrelor, two reversible ligands to P2Y12 receptor with longer half-life, may be at a higher risk of bleeding than those treated with acetylsalicylic acid alone, an irreversible ligand to COX-1. Results: Out of 1171 adult patients with incident primary ITP included in the registry during the study period, 143 (12.2%) were exposed to an antiplatelet drug at the time of ITP diagnosis: 108 to acetylsalicylic acid alone, 20 to clopidogrel alone and 15 to an association of antiplatelet agents (acetylsalicylic acid + clopidogrel, n=13; acetylsalicylic acid + ticagrelor, n=2). In the acetylsalicylic acid group, the median age was 75.5 years, 73 (67.6%) were men, median platelet count at ITP diagnosis was 15 x 109/L and 66 (61.1%) had bleeding: 60 (55.6%) a cutaneous bleeding, 35 (32.4%) a non-serious mucosal bleeding and 4 (3.7%) a serious bleeding (3 gastrointestinal bleeding with anemia and 1 gross hematuria with anemia). The pattern of bleeding by platelet count categories is shown in Figure 1. The frequency of overall bleeding was 97.6% (41/42) in the < 10 x 109/L group, 66.7% (14/21) in the 10 - 19 x 109/L group and 22.2% (10/45) in the ≥20 x 109/L group (similar pattern by all categories ≥20 x 109/L). The receiver operating characteristics curve had an area under the curve of 88.3% (95% confidence interval: 81.9-94.6%). The threshold of <20 x 109/L had a sensitivity of 83.3% and a specificity of 81.0%. The pattern for cutaneous and non-serious mucosal bleeding was similar (Figure 1). All four serious bleeding occurred in patients with a platelet count <20 x 109/L. In the clopidogrel and association of antiplatelet drug groups, bleeding was observed in 14 (70.0%) and 10 (66.7%) patients, respectively. No clear correlation with the platelet count was shown, limited by the low number of patients. One serious bleeding occurred in each group (two intracranial bleeding), in patients with platelet counts < 10 x 109/L. Conclusion: This study shows that the bleeding risk in ITP patients treated with acetylsalicylic acid alone is similar to other ITP patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Shape-selective separation of copper nanowires and copper-based nanoparticles by a ligand exchange strategy

Copper nanowires (Cu NWs) have been regarded as one of the most potential materials in the field of optoelectronics. However, the performance of Cu NWs based devices are directly affected by the purity of the Cu NWs, which mainly depends on the containing copper nanoparticle (Cu NPs). Here, we developed a novel shape-selective approach by a reversible ligand exchange process that simultaneously satisfies the high efficiency, high selectivity, and less deterioration of the target Cu NWs. Due to the difference in ligand exchange rates between Cu NWs and Cu NPs, the Cu NWs kept be hydrophobic and spontaneously floated up to the interface between the aqueous solution of organic additive and air, while the Cu NPs turned to be hydrophilic and dispersed evenly in the solution. Using sodium 3-mercaptopropanesulphonate as the ligand exchange reagent, the Cu NWs and Cu NPs can be separated efficiently under the optimal operation conditions. The organic additive can be screened according to the surface tension of the solution and easily available. Besides, this strategy is applicable to effectively separate Cu NWs from Cu@Ag NPs and Ni@Cu NPs. This method based on the ligand exchange is expected to promote the shape-selective separation of nanomaterials.

Reversible Oxidative Addition of Zinc Hydride at a Gallium(I)-Centre: Labile Mono- and Bis(hydridogallyl)zinc Complexes.

In the presence of TMEDA (N,N,N',N'-tetramethylethylenediamine), partially deaggregated zinc dihydride as hydrocarbon suspensions react with the gallium(I) compound [(BDI)Ga] (I, BDI={HC(C(CH3 )N(2,6-iPr2 -C6 H3 ))2 }- ) by formal oxidative addition of a Zn-H bond to the gallium(I) centre. Dissociation of the labile TMEDA ligand in the resulting complex [(BDI)Ga(H)-(H)Zn(tmeda)] (1) facilitates insertion of a second equiv. of I into the remaining Zn-H to form a thermally sensitive trinuclear species [{(BDI)Ga(H)}2 Zn] (2). Compound 1 exchanges with polymeric zinc dideuteride [ZnD2 ]n in the presence of TMEDA, and with compounds I and 2 via sequential and reversible ligand dissociation and gallium(I) insertion. Spectroscopic and computational studies demonstrate the reversibility of oxidative addition of each Zn-H bond to the gallium(I) centres.

Lysine-Targeted Reversible Covalent Ligand Discovery for Proteins via Phage Display.

Binding via reversible covalent bond formation presents a novel and powerful mechanism to enhance the potency of synthetic inhibitors for therapeutically important proteins. Work on this front has yielded the anticancer drug bortezomib as well as the antisickling drug voxelotor. However, the rational design of reversible covalent inhibitors remains difficult even when noncovalent inhibitors are available as a scaffold. Herein, we report chemically modified phage libraries, both linear and cyclic, that incorporate 2-acetylphenylboronic acid (APBA) as a warhead to bind lysines via reversible iminoboronate formation. To demonstrate their utility, these APBA-presenting phage libraries were screened against sortase A of Staphylococcus aureus, as well as the spike protein of SARS-CoV-2. For both protein targets, peptide ligands were readily identified with single-digit micromolar potency and excellent specificity, enabling live-cell sortase inhibition and highly sensitive spike protein detection, respectively. Furthermore, our structure-activity studies unambiguously demonstrate the benefit of the APBA warhead for protein binding. Overall, this contribution shows for the first time that reversible covalent inhibitors can be developed via phage display for a protein of interest. The phage display platform should be widely applicable to proteins including those involved in protein-protein interactions.

Selective and Reversible Ligand Assembly on the DNA and RNA Repeat Sequences in Myotonic Dystrophy.

Small molecule targeting of DNA and RNA sequences has come into focus as a therapeutic strategy for diseases such as myotonic dystrophy type 1 (DM1), a trinucleotide repeat disease characterized by RNA gain-of-function. Herein, we report a novel template-selected, reversible assembly of therapeutic agents in situ via aldehyde-amine condensation. Rationally designed small molecule targeting agents functionalized with either an aldehyde or an amine were synthesized and screened against the target nucleic acid sequence. The assembly of fragments was confirmed by MALDI-MS in the presence of DM1-relevant nucleic acid sequences. The resulting hit combinations of aldehyde and amine inhibited the formation of r(CUG)exp in vitro in a cooperative manner at low micromolar levels and rescued mis-splicing defects in DM1 model cells. This reversible template-selected assembly is a promising approach to achieve cell permeable and multivalent targeting via in situ synthesis and could be applied to other nucleic acid targets.

A novel monoacylglycerol lipase-targeted 18F-labeled probe for positron emission tomography imaging of brown adipose tissue in the energy network.

Monoacylglycerol lipase (MAGL) constitutes a serine hydrolase that orchestrates endocannabinoid homeostasis and exerts its function by catalyzing the degradation of 2-arachidonoylglycerol (2-AG) to arachidonic acid (AA). As such, selective inhibition of MAGL represents a potential therapeutic and diagnostic approach to various pathologies including neurodegenerative disorders, metabolic diseases and cancers. Based on a unique 4-piperidinyl azetidine diamide scaffold, we developed a reversible and peripheral-specific radiofluorinated MAGL PET ligand [18F]FEPAD. Pharmacokinetics and binding studies on [18F]FEPAD revealed its outstanding specificity and selectivity towards MAGL in brown adipose tissue (BAT) - a tissue that is known to be metabolically active. We employed [18F]FEPAD in PET studies to assess the abundancy of MAGL in BAT deposits of mice and found a remarkable degree of specific tracer binding in the BAT, which was confirmed by post-mortem tissue analysis. Given the negative regulation of endocannabinoids on the metabolic BAT activity, our study supports the concept that dysregulation of MAGL is likely linked to metabolic disorders. Further, we now provide a suitable imaging tool that allows non-invasive assessment of MAGL in BAT deposits, thereby paving the way for detailed mechanistic studies on the role of BAT in endocannabinoid system (ECS)-related pathologies.

Cobalt(II)-tetraphenylporphyrin-catalysed carbene transfer from acceptor-acceptor iodonium ylides via N-enolate-carbene radicals.

Square-planar cobalt(II) systems have emerged as powerful carbene transfer catalysts for the synthesis of numerous (hetero)cyclic compounds via cobalt(III)-carbene radical intermediates. Spectroscopic detection and characterization of reactive carbene radical intermediates is limited to a few scattered experiments, centered around monosubstituted carbenes. Here, we reveal the formation of disubstituted cobalt(III)-carbene radicals derived from a cobalt(II)-tetraphenylporphyrin complex and acceptor-acceptor λ3-iodaneylidenes (iodonium ylides) as carbene precursors and their catalytic application. Iodonium ylides generate biscarbenoid species via reversible ligand modification of the paramagnetic cobalt(II)-tetraphenylporphyrin complex catalyst. Two interconnected catalytic cycles are involved in the overall mechanism, with a monocarbene radical and an N-enolate-carbene radical intermediate at the heart of each respective cycle. Notably, N-enolate formation is not a deactivation pathway but a reversible process, enabling transfer of two carbene moieties from a single N-enolate-carbene radical intermediate. The findings are supported by extensive experimental and computational studies.

Monte Carlo simulations of the self-assembly of hierarchically organized metal-organic networks on solid surfaces

The coordination-driven self-assembly of two-dimensional (2D) supramolecular architectures is a convenient method of rational construction of one-atom-thick nanomaterials with desired topology, intriguing physicochemical properties and high cognitive value. In this work, we use coarse-grained Monte Carlo (MC) computer simulations to study the self-assembly of functional bridging ligands with mononuclear metal centers on a triangular lattice. Particularly, we focus on the role of anisotropic, reversible ligand → metal coordinate bonds in the bottom-up formation of hierarchically organized metal-organic networks composed of star-shaped and rod-like linkers (representing real organic molecules) and trivalent metal atoms. In our model π aromatic ligands were modeled in a simplified way as a collection of flat, rigid, and interconnected segments with properly encoded short-ranged interactions. Depending on the composition of the investigated overlayers, we observed the spontaneous formation a cascade of openwork (co)crystals with a hierarchical structure, controllable chirality and scalable morphological properties like porosity, connectivity, density, etc. Our theoretical findings can pave the way for the experimental fabrication of the novel surface-confined metal-organic networks (SMONs) in which anisotropic coordinate bonds play a decisive role.

Analysis of human Tribbles 2 (TRIB2) pseudokinase.

Human Tribbles 2 (TRIB2) is a cancer-associated pseudokinase with a broad human protein interactome, including the well-studied AKT, C/EBPα and MAPK modules. Several lines of evidence indicate that human TRIB2 promotes cell survival and drug-resistance in solid tumors and blood cancers and is therefore of interest as a potential therapeutic target, although its physiological functions remain relatively poorly understood. The unique TRIB2 pseudokinase domain lacks the canonical 'DFG' motif, and subsequently possesses very low affinity for ATP in both the presence and absence of metal ions. However, TRIB2 also contains a unique cysteine-rich αC-helix, which interacts with a conserved peptide motif in its own carboxyl-terminal tail. This regulatory flanking region drives regulated interactions with distinct E3 ubiquitin ligases that serve to control the stability and turnover of TRIB2 client proteins. TRIB2 is also a low-affinity target of several known small-molecule protein kinase inhibitors, which were originally identified using purified recombinant TRIB2 proteins and a thermal shift assay. In this chapter, we discuss laboratory-based procedures for purification, stabilization and analysis of human TRIB2, including screening procedures that can be used for the identification of both reversible and covalent small molecule ligands.

Reversible Ligand Exchange of Triphenylphosphine with Thiols on Gold Nanoparticles for Janus Modification and Catalyst Recycling

Reversible Ligand Exchange of Triphenylphosphine with Thiols on Gold Nanoparticles for Janus Modification and Catalyst Recycling