Small Molecule Mimetics of α-Helical Domain of IRAK2 Attenuate the Proinflammatory Effects of IL-33 in Asthma-like Mouse Models.

IL-33 and its receptor ST2 play important roles in airway inflammation and contribute to asthma onset and exacerbation. The IL-33/ST2 signaling pathway recruits adapter protein myeloid differentiation primary response 88 (MyD88) to transduce intracellular signaling. MyD88 forms a complex with IL-R-associated kinases (IRAKs), IRAK4 and IRAK2, called the Myddosome (MyD88-IRAK4-IRAK2).

Rational design of peptide derivatives for inhibition of MyD88-mediated toll-like receptor signaling in human peripheral blood mononuclear cells and epithelial cells exposed to Francisella tularensis.

Small molecules were developed to attenuate proinflammatory cytokines resulting from activation of MyD88-mediated toll-like receptor (TLR) signaling by Francisella tularensis. Fifty-three tripeptide derivatives were synthesized to mimic a key BB-loop region involved in toll-like/interleukin-1 receptor recognition (TIR) domain interactions. Compounds were tested for inhibition of TNF-α, IFN-γ, IL-6, and IL-1β in human peripheral blood mononuclear cells (PBMCs) and primary human bronchial epithelial cells exposed to LPS extracts from F.

Recognition and sequestration of ω-fatty acids by a cavitand receptor.

One of the largest driving forces for molecular association in aqueous solution is the hydrophobic effect, and many synthetic receptors with hydrophobic interiors have been devised for molecular recognition studies in water. Attempts to create the longer, narrower cavities appropriate for long-chain fatty acids have been thwarted by solvophobic collapse of the synthetic receptors, giving structures that have no internal spaces. The collapse generally involves the stacking of aromatic panels onto themselves.

Synapse-specific IL-1 receptor subunit reconfiguration augments vulnerability to IL-1β in the aged hippocampus.

In the aged brain, synaptic plasticity and memory show increased vulnerability to impairment by the inflammatory cytokine interleukin 1β (IL-1β). In this study, we evaluated the possibility that synapses may directly undergo maladaptive changes with age that augment sensitivity to IL-1β impairment. In hippocampal neuronal cultures, IL-1β increased the expression of the IL-1 receptor type 1 and the accessory coreceptor AcP (proinflammatory), but not of the AcPb (prosurvival) subunit, a reconfiguration that potentiates the responsiveness of neurons to IL-1β.

Structure-Based Design and Synthesis of a Small Molecule that Exhibits Anti-inflammatory Activity by Inhibition of MyD88-mediated Signaling to Bacterial Toxin Exposure.

Both Gram-positive and Gram-negative pathogens or pathogen-derived components, such as staphylococcal enterotoxins (SEs) and endotoxin (LPS) exposure, activate MyD88-mediated pro-inflammatory cellular immunity for host defense. However, dysregulated MyD88-mediated signaling triggers exaggerated immune response that often leads to toxic shock and death. Previously, we reported a small molecule compound 1 mimicking BB-loop structure of MyD88 was capable of inhibiting pro-inflammatory response to SEB exposure in mice.

Folded alkyl chains in water-soluble capsules and cavitands.

A deep cavitand with ionic "feet" dimerizes around hydrophobic compounds in D2O. Longer n-alkane guests, C14-C18, are encapsulated in contorted conformations and NMR is used to deduce their shapes. Competition experiments establish the driving forces involved and how they compensate for the steric clashes in the folded structures of the encapsulated alkanes.

Soft templates in encapsulation complexes.

Template effects are an inevitable feature of supramolecular chemistry and were prominent in the discovery of crown ethers, carcerands and catenanes. Templates can act as guests or hosts, but in either role they must be structurally persistent - rigid or "hard" - on the timescale needed to form the final complexes. This report explores a peculiar effect encountered with self-assembled container molecules: soft templates.

Complexation of alkyl groups and ghrelin in a deep, water-soluble cavitand.

A cavitand with ionic, but nonionizable "feet" folds around hydrophobic guests in D2O. Short alkanes and ibuprofen are included and exchange rates are slow on the NMR timescale. Normal octanoyl groups show good affinity for the cavitand and the gastric peptide ghrelin is bound at low pH and physiological temperature.

Alkyl groups fold to fit within a water-soluble cavitand.

We report here a widened, deep cavitand host that binds hydrophobic and amphiphilic guests in D2O. Small alkanes (C6 to C11) are bound in compressed conformations and tumble rapidly within the space. Longer n-alkanes (C13 to C14), n-alcohols, and α,ω-diols are taken up in folded conformations.

Hydrogen-bonded capsules in water.

Hydrogen-bonded capsules constrain molecules into small spaces, where they exhibit behavior that is inaccessible in bulk solution. Water competes with the formation of hydrogen bonds, and other forces for assembly, such as metal/ligand interactions or hydrophobic effects, have been applied. Here we report the reversible assembly of a water-soluble cavitand to a robust capsule host in the presence of suitable hydrophobic guests.

Social isomers of picolines in a small space.

Encapsulation complexes permit the observation of molecules under conditions of limited motion. Inside capsules, molecular encounters are prolonged, prearranged, and protected from the medium, in contrast to the short-lived and random encounters that occur in bulk solution. Herein, the interaction of α-, β-, and γ-picolines in a cylindrical capsule is described.

Amplified halogen bonding in a small space.

Weak, intermolecular forces are difficult to observe in solution because the molecular encounters are random, short-lived, and overwhelmed by the solvent. In confined spaces such as capsules and the active sites of enzymes or receptors, the encounters are prolonged, prearranged, and isolated from the medium. We report here the application of encapsulation techniques to directly observe halogen bonding.

Chemical approaches for detection and destruction of nerve agents.

Since the introduction of organophosphorus (OP) compounds as nerve agents and pesticides, methods of dealing with their toxicity to humans have been intensely researched. There are studies on sensing, pretreatments, prophylactics, antidotes and therapies. There is some overlap in all of these endeavors because they have to deal with the reactivity of the phosphorus atom in various contexts.

Catalytic detoxification of nerve agent and pesticide organophosphates by butyrylcholinesterase assisted with non-pyridinium oximes.

In the present paper we show a comprehensive in vitro, ex vivo and in vivo study on hydrolytic detoxification of nerve agent and pesticide OPs (organophosphates) catalysed by purified hBChE (human butyrylcholinesterase) in combination with novel non-pyridinium oxime reactivators. We identified TAB2OH (2-trimethylammonio-6-hydroxybenzaldehyde oxime) as an efficient reactivator of OP-hBChE conjugates formed by the nerve agents VX and cyclosarin, and the pesticide paraoxon. It was also functional in reactivation of sarin- and tabun-inhibited hBChE.

Deep cavitands featuring functional acetal-based walls.

The synthesis of deep cavitands with functionalized acetals as a fourth-wall is described. Recognition properties and stabilities of the complexes of two representative cavitands with aliphatic, aromatic, carbocyclic and adamantane guests were evaluated by NMR methods.

Therapeutic inhibition of pro-inflammatory signaling and toxicity to staphylococcal enterotoxin B by a synthetic dimeric BB-loop mimetic of MyD88.

Staphylococcal enterotoxin B (SEB) exposure triggers an exaggerated pro-inflammatory cytokine response that often leads to toxic shock syndrome (TSS) associated with organ failure and death. MyD88 mediates pro-inflammatory cytokine signaling induced by SEB exposure and MyD88(-/-) mice are resistant to SEB intoxication, suggesting that MyD88 may be a potential target for therapeutic intervention. We targeted the BB loop region of the Toll/IL-1 receptor (TIR) domain of MyD88 to develop small-molecule therapeutics.

Hydration of isocyanates in an expandable, self-assembled capsule.

A self-assembled capsule facilitates reactions of isocyanates with water. The capsule provides an amphiphilic environment with hydrophobic aromatic ends and hydrophilic glycoluril units at the center. Reaction takes place in the narrow, cylindrical space to form the N,N-dialkylurea, which then appears in a longer capsule.

Encapsulation of ion pairs in extended, self-assembled structures.

Encapsulation of ion pairs in small spaces that are isolated from the medium is expected to result in amplified interactions between the ions. Yet, sequestration of ion pairs in self-assembled capsules is complicated by competition of the acids and bases for binding directly to the assembly components. We describe here a hydrogen-bonded capsule 1.

More chemistry in small spaces.

This Account is about coaxing molecules into spaces barely big enough to contain them: encapsulation complexes. In capsules, synthetic modules assemble to fold around their molecular targets, isolate them from the medium for relatively long times, place them in a hydrophobic environment, and present them with functional groups. These arrangements also exist in the interior spaces of biology, and the consequences include the familiar features of enzymes: rapid reactions, stabilization of reactive intermediates, and catalysis.

Alkane lengths determine encapsulation rates and equilibria.

A cylindrical capsule provides an environment for straight-chain alkanes that can properly fill the space through extended or compressed conformations. The encapsulation rates of a series of alkanes were examined and found to be dependent on guest length: the rates of uptake are C(9) > C(10) > C(11), while complex stability is in the reverse order, C(11) > C(10) > C(9). Direct competition experiments, pairwise or between all 3 alkanes, maintain this order as the longer alkanes sequentially displace the shorter ones.

Conformations and fluorescence of encapsulated stilbene.

Absorption and emission spectra of free and encapsulated stilbene in two different capsules were calculated using the DFT and the TDDFT methodology at the B3LYP, CAM-B3LYP, M06-2X, PBE0, and ωB97X-D/6-31G(d,p) levels of theory. The present work is directed toward the theoretical interpretation of recent experimental results on control of stilbene conformation and fluorescence in capsules [Ams, M. R.

Protein recognition by a self-assembled deep cavitand monolayer on a gold substrate.

This paper details the first use of a self-folding deep cavitand on a gold surface. A sulfide-footed deep, self-folding cavitand has been synthesized, and its attachment to a cleaned gold surface studied by electrochemical and SPR methods. Complete monolayer formation is possible if the cavitand folding is templated by noncovalent binding of choline or by addition of space-filling thiols to cover any gaps in the cavitand adsorption layer.

Reversibly expanded encapsulation complexes.

Synthetic receptors that surround their target molecules - self assembled capsules and deep cavitands - have emerged as the most realistic models of enzymes active sites. They were introduced to study the behaviour of molecules isolated in small spaces and it has become increasingly clear that the behavior of molecules in dilute aqueous solution does not reflect their behavior in confimed spaces. The synthetic receptors fold around their target guests, isolate them from the bulk solvent, provide a hydrophobic environment and present the guests with each other in a limited space.