Interference of the T Cell and Antigen-Presenting Cell Costimulatory Pathway Using CTLA4-Ig (Abatacept) Prevents Staphylococcal Enterotoxin B Pathology.

Staphylococcal enterotoxin B (SEB) is a bacterial superantigen that binds the receptors in the APC/T cell synapse and causes increased proliferation of T cells and a cytokine storm syndrome in vivo. Exposure to the toxin can be lethal and cause significant pathology in humans. The lack of effective therapies for SEB exposure remains an area of concern, particularly in scenarios of acute mass casualties. We hypothesized that blockade of the T cell costimulatory signal by the CTLA4-Ig synthetic protein (abatacept) could prevent SEB-dependent pathology. In this article, we demonstrate mice treated with a single dose of abatacept 8 h post SEB exposure had reduced pathology compared with control SEB-exposed mice. SEB-exposed mice showed significant reductions in body weight between days 4 and 9, whereas mice exposed to SEB and also treated with abatacept showed no weight loss for the duration of the study, suggesting therapeutic mitigation of SEB-induced morbidity. Histopathology and magnetic resonance imaging demonstrated that SEB mediated lung damage and edema, which were absent after treatment with abatacept. Analysis of plasma and lung tissues from SEB-exposed mice treated with abatacept demonstrated significantly lower levels of IL-6 and IFN-γ (p < 0.0001), which is likely to have resulted in less pathology. In addition, exposure of human and mouse PBMCs to SEB in vitro showed a significant reduction in levels of IL-2 (p < 0.0001) after treatment with abatacept, indicating that T cell proliferation is the main target for intervention. Our findings demonstrate that abatacept is a robust and potentially credible drug to prevent toxic effects from SEB exposure.

Computational modelling of solvent effects in a prolific solvatomorphic porous organic cage.

Crystal structure prediction methods can enable the in silico design of functional molecular crystals, but solvent effects can have a major influence on relative lattice energies, sometimes thwarting predictions. This is particularly true for porous solids, where solvent included in the pores can have an important energetic contribution. We present a Monte Carlo solvent insertion procedure for predicting the solvent filling of porous structures from crystal structure prediction landscapes, tested using a highly solvatomorphic porous organic cage molecule, CC1. Using this method, we can understand why the predicted global energy minimum structure for CC1 is never observed from solvent crystallisation. We also explain the formation of three different solvatomorphs of CC1 from three structurally-similar chlorinated solvents. Calculated solvent stabilisation energies are found to correlate with experimental results from thermogravimetric analysis, suggesting a future computational framework for a priori materials design that factors in solvation effects.

Modular and predictable assembly of porous organic molecular crystals.

Nanoporous molecular frameworks are important in applications such as separation, storage and catalysis. Empirical rules exist for their assembly but it is still challenging to place and segregate functionality in three-dimensional porous solids in a predictable way. Indeed, recent studies of mixed crystalline frameworks suggest a preference for the statistical distribution of functionalities throughout the pores rather than, for example, the functional group localization found in the reactive sites of enzymes. This is a potential limitation for 'one-pot' chemical syntheses of porous frameworks from simple starting materials. An alternative strategy is to prepare porous solids from synthetically preorganized molecular pores. In principle, functional organic pore modules could be covalently prefabricated and then assembled to produce materials with specific properties. However, this vision of mix-and-match assembly is far from being realized, not least because of the challenge in reliably predicting three-dimensional structures for molecular crystals, which lack the strong directional bonding found in networks. Here we show that highly porous crystalline solids can be produced by mixing different organic cage modules that self-assemble by means of chiral recognition. The structures of the resulting materials can be predicted computationally, allowing in silico materials design strategies. The constituent pore modules are synthesized in high yields on gram scales in a one-step reaction. Assembly of the porous co-crystals is as simple as combining the modules in solution and removing the solvent. In some cases, the chiral recognition between modules can be exploited to produce porous organic nanoparticles. We show that the method is valid for four different cage modules and can in principle be generalized in a computationally predictable manner based on a lock-and-key assembly between modules.

Acid- and base-stable porous organic cages: shape persistence and pH stability via post-synthetic "tying" of a flexible amine cage.

Imine cage molecules can be reduced to amines to improve their chemical stability, but this introduces molecular flexibility. Hence, amine cages tend not to exhibit permanent solid-state porosity. We report a synthetic strategy to achieve shape persistence in amine cages by tying the cage vertices with carbonyls such as formaldehyde. Shape persistence is predicted by conformer stability calculations, providing a design basis for the strategy. The tied cages show enhanced porosity and unprecedented chemical stability toward acidic and basic conditions (pH 1.7-12.3), where many other porous crystalline solids would fail.

On crystal versus fiber formation in dipeptide hydrogelator systems.

Naphthalene dipeptides have been shown to be useful low-molecular-weight gelators. Here we have used a library to explore the relationship between the dipeptide sequence and the hydrogelation efficiency. A number of the naphthalene dipeptides are crystallizable from water, enabling us to investigate the comparison between the gel/fiber phase and the crystal phase. We succeeded in crystallizing one example directly from the gel phase. Using X-ray crystallography, molecular modeling, and X-ray fiber diffraction, we show that the molecular packing of this crystal structure differs from the structure of the gel/fiber phase. Although the crystal structures may provide important insights into stabilizing interactions, our analysis indicates a rearrangement of structural packing within the fibers. These observations are consistent with the fibrillar interactions and interatomic separations promoting 1D assembly whereas in the crystals the peptides are aligned along multiple axes, allowing 3D growth. This observation has an impact on the use of crystal structures to determine supramolecular synthons for gelators.

Supramolecular engineering of intrinsic and extrinsic porosity in covalent organic cages.

Control over pore size, shape, and connectivity in synthetic porous materials is important in applications such as separation, storage, and catalysis. Crystalline organic cage molecules can exhibit permanent porosity, but there are few synthetic methods to control the crystal packing and hence the pore connectivity. Typically, porosity is either 'intrinsic' (within the molecules) or 'extrinsic' (between the molecules)--but not both. We report a supramolecular approach to the assembly of porous organic cages which involves bulky directing groups that frustrate the crystal packing. This generates, in a synthetically designed fashion, additional 'extrinsic' porosity between the intrinsically porous cage units. One of the molecular crystals exhibits an apparent Brunauer-Emmett-Teller surface area of 854 m(2) g(-1), which is higher than that of unfunctionalized cages of the same dimensions. Moreover, connectivity between pores, and hence guest uptakes, can be modulated by the introduction of halogen bonding motifs in the cage modules. This suggests a broader approach to the supramolecular engineering of porosity in molecular organic crystals.

Conformer interconversion in a switchable porous organic cage.

Porous organic cage crystals can show unique properties, such as switching from being porous to non-porous in the solid state. Conformer interconversion plays a crucial role in this for the imine cage molecule, CC1. The barriers to interconversion were calculated and found to match experimentally determined values. Calculations suggest that solvent interactions reduce these activation barriers.

A guest-responsive fluorescent 3D microporous metal-organic framework derived from a long-lifetime pyrene core.

The carboxylate ligand 1,3,6,8-tetrakis(p-benzoic acid)pyrene (TBAPy)-based on the strongly fluorescent long-lifetime pyrene core-affords a permanently microporous fluorescent metal-organic framework, [In(2)(OH)(2)(TBAPy)].(guests) (1), displaying 54% total accessible volume and excellent thermal stability. Fluorescence studies reveal that both 1 and TBAPy display strong emission bands at 471 and 529 nm, respectively, upon excitation at 390 nm, with framework coordination of the TBAPy ligands significantly increasing the emission lifetime from 0.089 to 0.110 ms. Upon desolvation, the emission band for the framework is shifted to lower energy: however, upon re-exposure to DMF the as-made material is regenerated with reversible fluorescence behavior. Together with the lifetime, the emission intensity is strongly enhanced by spatial separation of the optically active ligand molecules within the MOF structure and is found to be dependent on the amount and chemical nature of the guest species in the pores. The quantum yield of the material is found to be 6.7% and, coupled with the fluorescence lifetime on the millisecond time scale, begins to approach the values observed for Eu(III)-cryptate-derived commercial sensors.

A metal-organic framework with a covalently prefabricated porous organic linker.

We report here the synthesis of a metal-organic framework comprising an organic cage linker with covalently prefabricated, intrinsic porosity. The network can be compared to a porous rock salt structure where the pores are partially filled by charge-balancing cations.

Porous organic cages.

Porous materials are important in a wide range of applications including molecular separations and catalysis. We demonstrate that covalently bonded organic cages can assemble into crystalline microporous materials. The porosity is prefabricated and intrinsic to the molecular cage structure, as opposed to being formed by non-covalent self-assembly of non-porous sub-units. The three-dimensional connectivity between the cage windows is controlled by varying the chemical functionality such that either non-porous or permanently porous assemblies can be produced. Surface areas and gas uptakes for the latter exceed comparable molecular solids. One of the cages can be converted by recrystallization to produce either porous or non-porous polymorphs with apparent Brunauer-Emmett-Teller surface areas of 550 and 23 m2 g(-1), respectively. These results suggest design principles for responsive porous organic solids and for the modular construction of extended materials from prefabricated molecular pores.

High surface area amorphous microporous poly(aryleneethynylene) networks using tetrahedral carbon- and silicon-centred monomers.

Poly(aryleneethynylene) networks prepared from tetrahedral monomers are highly microporous and exhibit apparent Brunauer-Emmett-Teller surface areas of up to 1213 m2 g(-1).

Magnesium borohydride confined in a metal-organic framework: a preorganized system for facile arene hydroboration.

In close quarters: When confined in a metal-organic framework, magnesium borohydride reacts with arenes by a hydroboration pathway (see scheme), in contrast to its reactivity under analogous homogeneous solution-phase conditions. Framework-imposed organization of the reactive groups is required, which is achieved by a combination of the metal coordination and two hydrogen bonds.

Synthetic control of the pore dimension and surface area in conjugated microporous polymer and copolymer networks.

A series of rigid microporous poly(aryleneethynylene) (PAE) networks was synthesized by Sonogashira-Hagihara coupling chemistry. PAEs with apparent Brunauer-Emmet-Teller surface areas of more than 1000 m(2)/g were produced. The materials were found to have very good chemical and thermal stability and retention of microporosity under a variety of conditions. It was shown that physical properties such as micropore size, surface area, and hydrogen uptake could be controlled in a "quantized" fashion by varying the monomer strut length, as for metal-organic and covalent organic frameworks, even though the networks were amorphous in nature. For the first time, it was demonstrated that these properties can also be fine-tuned in a continuous manner via statistical copolymerization of monomer struts with differing lengths. This provides an unprecedented degree of direct synthetic control over micropore properties in an organic network.

Potency of irritation by benzylidenemalononitriles in humans correlates with TRPA1 ion channel activation.

We show that the physiological activity of solid aerosolized benzylidenemalononitriles (BMNs) including 'tear gas' (CS) in historic human volunteer trials correlates with activation of the human transient receptor potential ankyrin 1 ion channel (hTRPA1). This suggests that the irritation caused by the most potent of these compounds results from activation of this channel. We prepared 50 BMNs and measured their hTRPA1 agonist potencies. A mechanism of action consistent with their physiological activity, involving their dissolution in water on contaminated body surfaces, cell membrane penetration and reversible thiolation by a cysteine residue of hTRPA1, supported by data from nuclear magnetic resonance experiments with a model thiol, explains the structure-activity relationships. The correlation provides evidence that hTRPA1 is a receptor for irritants on nociceptive neurons involved in pain perception; thus, its activation in the eye, nose, mouth and skin would explain the symptoms of lachrymation, sneezing, coughing and stinging, respectively. The structure-activity results and the use of the BMNs as pharmacological tools in future by other researchers may contribute to a better understanding of the TRPA1 channel in humans (and other animals) and help facilitate the discovery of treatments for human diseases involving this receptor.

Trapping virtual pores by crystal retro-engineering.

Stable guest-free porous molecular crystals are uncommon. By contrast, organic molecular crystals with guest-occupied cavities are frequently observed, but these cavities tend to be unstable and collapse on removal of the guests-this feature has been referred to as 'virtual porosity'. Here, we show how we have trapped the virtual porosity in an unstable low-density organic molecular crystal by introducing a second molecule that matches the size and shape of the unstable voids. We call this strategy 'retro-engineering' because it parallels organic retrosynthetic analysis, and it allows the metastable two-dimensional hexagonal pore structure in an organic solvate to be trapped in a binary cocrystal. Unlike the crystal with virtual porosity, the cocrystal material remains single crystalline and porous after removal of guests by heating.

Selective gas sorption in a [2+3] 'propeller' cage crystal.

A [2+3] organic cage compound based on the condensation reaction of 1,3,5-tri(4-formylphenyl)benzene with 1,5-pentanediamine was synthesized. The resulting porous molecular crystal demonstrates selective adsorption of hydrogen and carbon dioxide over nitrogen. As for porous polymer membranes, a trade-off between sorption capacity and selectivity is observed for materials in this class.