Synthetic mimics of biotin/(strept)avidin Liu, Wenqi; Samanta, Soumen K; Smith, Bradley D ...
Chemical Society reviews,
05/2017, Letnik:
46, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Biotin/(strept)avidin self-assembly is a powerful platform for nanoscale fabrication and capture with many different applications in science, medicine, and nanotechnology. However, ...biotin/(strept)avidin self-assembly has several well-recognized drawbacks that limit performance in certain technical areas and there is a need for synthetic mimics that can either become superior replacements or operational partners with bio-orthogonal recognition properties. The goal of this tutorial review is to describe the recent progress in making high affinity synthetic association partners that operate in water or biological media. The review starts with a background summary of biotin/(strept)avidin self-assembly and the current design rules for creating synthetic mimics. A series of case studies are presented that describe recent success using synthetic derivatives of cyclodextrins, cucurbiturils, and various organic cyclophanes such as calixarenes, deep cavitands, pillararenes, and tetralactams. In some cases, two complementary partners associate to produce a nanoscale complex and in other cases a ditopic host molecule is used to link two partners. The article concludes with a short discussion of future directions and likely challenges.
One of the major goals of modern supramolecular chemistry, with important practical relevance in many technical fields, is the development of synthetic host/guest partners with ultrahigh affinity and ...selectivity in water. Currently, most association pairs exhibit micromolar affinity or weaker, and there are very few host/guest systems with K a > 109 M–1, apparently due to a barrier imposed by enthalpy/entropy compensation. This present study investigated the threading of a water-soluble tetralactam cyclophane by a deep-red fluorescent squaraine guest with flanking polyethylene glycol chains, an association process that is dominated by a highly favorable enthalpic driving force. A squaraine structure was rationally designed to permit guest back-folding as a strategy to greatly expand the hydrophobic surface area that could be buried upon complexation. Guided by computational modeling, an increasing number of N-benzyl groups were appended to the squaraine core, so that, after threading, the aromatic rings could fold back and stack against the cyclophane periphery. The final design iteration exhibited an impressive combination of fluorescence and supramolecular properties, including ratiometric change in deep-red emission, picomolar affinity (K a = 5.1 × 1010 M–1), and very rapid threading (k on = 7.9 × 107 M–1 s–1) in water at 25 °C. Similar excellent behavior was observed in serum solution. A tangible outcome of this study is a new cyclophane/squaraine association pair that will be a versatile platform for many different types of fluorescence-based imaging and diagnostics applications. From a broader perspective, guest back-folding of aromatic groups is a promising new supramolecular stabilization strategy to overcome enthalpy/entropy compensation and produce ultrahigh affinity 2pseudorotaxane complexes in water and biological media.
The near‐infrared window of fluorescent heptamethine cyanine dyes greatly facilitates biological imaging because there is deep penetration of the light and negligible background fluorescence. ...However, dye instability, aggregation, and poor pharmacokinetics are current drawbacks that limit performance and the scope of possible applications. All these limitations are simultaneously overcome with a new molecular design strategy that produces a charge balanced and sterically shielded fluorochrome. The key design feature is a meso‐aryl group that simultaneously projects two shielding arms directly over each face of a linear heptamethine polyene. Cell and mouse imaging experiments compared a shielded heptamethine cyanine dye (and several peptide and antibody bioconjugates) to benchmark heptamethine dyes and found that the shielded systems possess an unsurpassed combination of photophysical, physiochemical, and biodistribution properties that greatly enhance bioimaging performance.
It's a bird! It's a plane! Just like a superhero, an ultrastable shielded heptamethine cyanine dye uses its two strong arms to ward off self‐aggregation and non‐specific biological interactions. Yet the arms are short enough to allow dye‐labeled bioconjugates to selectively target cell receptors for high‐contrast and photon‐intense microscopy or tumor imaging in living subjects.
When can diplomatic communication facilitate military cooperation? I analyze a formal model in which states may form coalitions for war but are uncertain about a partner’s willingness to fight. I ...demonstrate that incentives to lie are greatest when potential coalition partners agree on how to settle a dispute. Additionally, the audience of communication matters. Communication among military partners is only credible when it occurs in private, out of view of a shared enemy. Taken together, the results indicate that preference heterogeneity and secrecy are necessary for credible communication among military partners. In an extension, I show that the availability of side payments exacerbates the difficulty of communication. The theoretical results provide a framework to understand observed variation in the success of precrisis diplomacy among potential coalition members.
This report describes cucurbit7uril (CB7) complexation of azobenzene dyes that have a 4-(N,N′-dimethylamino) or 4-amino substituent. Absorption and NMR data show that CB7 encapsulates the protonated ...form of the azobenzene and that the complexed dye exists as its azonium tautomer with a trans azo conformation and substantial quinoid resonance character. Because CB7 complexation stabilizes the dye conjugate acid, there is an upward shift in its pK a, and in one specific case, the pK a of the protonated azobenzene is increased from 3.09 to 4.47. Molecular modeling indicates that the CB7/azobenzene complex is stabilized by three major noncovalent factors: (i) ion-dipole interactions between the partially cationic 4-(N,N′-dimethylamino) or 4-amino group on the encapsulated protonated azobenzene and the electronegative carbonyl oxygens on CB7, (ii) inclusion of the upper aryl ring of the azobenzene within the hydrophobic CB7 cavity, and (iii) a hydrogen bond between the proton on the azo nitrogen and CB7 carbonyls. CB7 complexation enhances azobenzene stability and increases azobenzene hydrophilicity; thus, it is a promising way to improve azobenzene performance as a pigment or prodrug. In addition, the striking yellow/pink color change that accompanies CB7 complexation can be exploited to create azobenzene dye displacement assays with naked eye detection.
Commitment Problems in Alliance Formation Benson, Brett V.; Smith, Bradley C.
American journal of political science,
10/2023, Letnik:
67, Številka:
4
Journal Article
Recenzirano
Abstract
If military alliances cause significant shifts in the distribution of power, why does anticipation of their formation or expansion provoke hostility from adversaries in some cases and not ...others? We develop a theory to explain this variation, advancing three arguments about the connection between alliances, commitment problems and war. First, we show that prospective allies can avoid provoking a common enemy by offering concessions to offset losses from an anticipated power shift from an alliance. Second, limits to an alliance's power or implementation speed may make such bargains possible. Allies manipulate these factors to set the terms of cooperation to avoid provoking a shared enemy. Finally, when such bargains are not possible, incentives for preventive war exist but the outbreak of such wars may be avoided. Although preventive war cannot be ruled out altogether, the conditions that make it most attractive also make it unlikely to be carried out.
The ABCA1 protein mediates the transfer of cellular cholesterol across the plasma membrane to apolipoprotein A-I. Loss-of-function mutations in the ABCA1 gene induce Tangier disease and familial ...hypoalphalipoproteinemia, both cardiovascular conditions characterized by abnormally low levels of serum cholesterol, increased cholesterol in macrophages, and subsequent formation of vascular plaque. Increased intracellular cholesterol levels are also frequently found in cancer cells. Here, we demonstrate anticancer activity of ABCA1 efflux function, which is compromised following inhibition of ABCA1 gene expression by oncogenic mutations or cancer-specific ABCA1 loss-of-function mutations. In concert with elevated cholesterol synthesis found in cancer cells, ABCA1 deficiency allows for increased mitochondrial cholesterol, inhibits release of mitochondrial cell death-promoting molecules, and thus facilitates cancer cell survival, suggesting that elevated mitochondrial cholesterol is essential to the cancer phenotype.
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► Cholesterol export deficiency plays a role in both cardiovascular disease and cancer ► Human colon cancer mutations in ABCA1 disable cholesterol-export function ► Excess cholesterol in mitochondria arrests suicide mechanism in cancer cells ► High membrane cholesterol in mitochondria blocks release of cell-death promoters
Deregulation of cholesterol homeostasis has been associated with multiple types of cancer. Genetic evidence providing a causal link between elevated cholesterol and carcinogenesis, however, has been lacking. Smith and Land show that the efflux function of the cholesterol exporter ABCA1 gene has anticancer activity. Their work supports a model in which increased cholesterol synthesis and ABCA1 loss of function cause elevated mitochondrial cholesterol. This prevents formation of mitochondrial transition pores and consequent cell death in response to stressors. Targeting mitochondrial cholesterol may thus augment cancer intervention and/or prevention strategies.
A general synthetic method creates a new class of covalently connected, self‐threaded, fluorescent molecular probes with figure‐eight topology, an encapsulated deep‐red fluorophore, and two ...peripheral peptide loops. The globular molecular shape and rigidified peptide loops enhance imaging performance by promoting water solubility, eliminating probe self‐aggregation, and increasing probe stability. Moreover, the peptide loops determine the affinity and selectivity for targets within complex biological samples such as cell culture, tissue histology slices, or living subjects. For example, a probe with cell‐penetrating peptide loops targets the surface of cell plasma membranes, whereas, a probe with bone‐targeting peptide loops selectively stains the skeleton within a living mouse. The unique combination of bright deep‐red fluorescence, high stability, and predictable peptide‐based targeting is ideal for photon intense fluorescence microscopy and biological imaging.
A fluorophore buried inside a self‐threaded peptide probe will promote high water solubility, lower the propensity for probe self‐aggregation, and greatly enhance probe stability. The peptide loops determine the affinity and selectivity for targets within complex biological samples such as cell culture, tissue histology slices, or living subjects.
The GGGGCC (G4C2) intronic repeat expansion within C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Intranuclear neuronal RNA ...foci have been observed in ALS and FTD tissues, suggesting that G4C2 RNA may be toxic. Here, we demonstrate that the expression of 38× and 72× G4C2 repeats form intranuclear RNA foci that initiate apoptotic cell death in neuronal cell lines and zebrafish embryos. The foci colocalize with a subset of RNA binding proteins, including SF2, SC35, and hnRNP-H in transfected cells. Only hnRNP-H binds directly to G4C2 repeats following RNA immunoprecipitation, and only hnRNP-H colocalizes with 70% of G4C2 RNA foci detected in C9ORF72 mutant ALS and FTD brain tissues. We show that expanded G4C2 repeats are potently neurotoxic and bind hnRNP-H and other RNA binding proteins. We propose that RNA toxicity and protein sequestration may disrupt RNA processing and contribute to neurodegeneration.
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•Longer G4C2 transcripts form neurotoxic RNA foci in cells and zebrafish•Longer G4C2 foci sequester RNA binding proteins hnRNP-H, SC35, and SF2•G4C2 RNA foci and hnRNP-H knockdown similarly affect TARBP2 splicing•Seventy percent of G4C2 RNA foci in C9ORF72 ALS/FTD brains colocalize with hnRNP-H
In this study, Shaw and colleagues explore mechanisms underlying toxicity of the expanded G4C2 hexanucleotide intronic repeat in C9ORF72, the most common known cause of ALS and FTD. Pathologically expanded G4C2 RNA transcripts form intranuclear foci, sequester specific RNA-binding proteins, and are potently toxic in transfected cells and zebrafish embryos. One protein, hnRNP-H, is detected in 70% of foci in C9ORF72 brain tissues, and loss of hnRNP-H leads to aberrant RNA splicing that could contribute to neurodegeneration.
Two macrocyclic tetralactam receptors are shown to selectively encapsulate anionic, square-planar chloride and bromide coordination complexes of gold(III), platinum(II), and palladium(II). Both ...receptors have a preorganized structure that is complementary to its precious metal guest. The receptors do not directly ligate the guest metal center but instead provide an array of arene π-electron donors that interact with the electropositive metal and hydrogen-bond donors that interact with the outer electronegative ligands. This unique mode of supramolecular recognition is illustrated by six X-ray crystal structures showing receptor encapsulation of AuCl4 –, AuBr4 –, PtCl4 –2, or Pd2Cl6 –2. In organic solution, the 1:1 association constants correlate with specific supramolecular features identified in the solid state. Technical applications using these receptors are envisioned in a wide range of fields that involve precious metals, including mining, recycling, catalysis, nanoscience, and medicine.
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