The Janus effect of colloidal self-assembly on the biological response of amphiphilic drugs.

In aqueous environment amphiphilic molecules organize themselves into supramolecular structures deeply affecting the chemo-physical properties. Supramolecular assemby is also crucial in the pharmaceutical development of bioactive lipophilic molecules whose attitude to self-aggregate is a recognized factor affecting the in vivo pharmacokinetic, but can also play a crucial role in the interaction with the biological targets in in vitro tests. In aqueous solution, amphiphilic drugs exist in a complex equilibrium involving free monomers, oligomers and larger supramolecular aggregates held together by noncovalent bonds. In this review we focus our attention on the dual effect of drugs self-assembly, which can both reduce the availability of active compounds and create multivalent scaffolds, potentially improving binding affinity and avidity to cellular targets. We examine the effect of aggregation on different classes of amphiphatic molecules with significant biological activities, such as immunomodulatory, anti-tumor, antiviral, and antibiotic. Our purpose is to provide a comprehensive overview of how supramolecular chemistry influences the pharmacological and biological responses of amphiphilic molecules, emphasizing the need to consider these effects in early-stage drug development and in vitro testing. By elucidating these phenomena, this review aims to offer insights into optimizing drug design and formulation to overcome challenges posed by self-aggregation.

Fused-Ring Electron-Acceptor Single Crystals with Chiral 2D Supramolecular Organization for Anisotropic Chiral Optoelectronic Devices.

Supramolecular chiral organization gives π-conjugated molecules access to fascinating specific interactions with circularly polarized light (CPL). Such a feature enables the fabrication of high-performance chiral organic electronic devices that detect or emit CPL directly. Herein, it is shown that chiral fused-ring electron-acceptor BTP-4F single-crystal-based phototransistors demonstrate distinguished CPL discrimination capability with current dissymmetry factor exceeding 1.4, one of the highest values among state-of-the-art direct CPL detectors. Theoretical calculations prove that the chirality at the supramolecular level in these enantiomeric single crystals originates from chiral exciton coupling of a unique quasi-2D supramolecular organization consisting of interlaced molecules with opposite helical conformation. Impressively, such supramolecular organization produces a higher dissymmetry factor along the preferred growth direction of the chiral single crystals in comparison to that of the short axis direction. Furthermore, the amplified, inverted, and also anisotropic current dissymmetry compared to optical dissymmetry is studied by finite element simulations. Therefore, a unique chiral supramolecular organization that is responsible for the excellent chiroptical response and anisotropic electronic properties is developed, which not only enables the construction of high-performance CPL detection devices but also allows a better understanding of the structure-property relationships in chiral organic optoelectronics.

Supramolecular Organization in Salts of Riluzole with Dihydroxybenzoic Acids-The Key Role of the Mutual Arrangement of OH Groups.

Intermolecular interactions, in particular hydrogen bonds, play a key role in crystal engineering. The ability to form hydrogen bonds of various types and strengths causes competition between supramolecular synthons in pharmaceutical multicomponent crystals. In this work, we investigate the influence of positional isomerism on the packing arrangements and the network of hydrogen bonds in multicomponent crystals of the drug riluzole with hydroxyl derivatives of salicylic acid. The supramolecular organization of the riluzole salt containing 2,6-dihydroxybenzoic acid differs from that of the solid forms with 2,4- and 2,5-dihydroxybenzoic acids. Because the second OH group is not at position 6 in the latter crystals, intermolecular charge-assisted hydrogen bonds are formed. According to periodic DFT calculations, the enthalpy of these H-bonds exceeds 30 kJ·mol-1. The positional isomerism appears to have little effect on the enthalpy of the primary supramolecular synthon (65-70 kJ·mol-1), but it does result in the formation of a two-dimensional network of hydrogen bonds and an increase in the overall lattice energy. According to the results of the present study, 2,6-dihydroxybenzoic acid can be treated as a promising counterion for the design of pharmaceutical multicomponent crystals.

The expression of chirality in linked poly(thiophene)s.

Conjugated polymers have demonstrated to express chirality, for instance, by strong circular dichroism (CD). However, the shape and intensity of the spectra can be quite different and are very difficult to predict. Molecular irregularity, star-shapes, and linking polymers have demonstrated to affect the CD, often in a positive way. In this research, we design two different chiral arms, in which the molecular irregularity results in a significantly different CD. Next, the arms are coupled to a linear core in all possible combinations. In this way, we demonstrate that rather small irregularities and linking arms to a central core increases CD, whereas heterogenous combinations result in smaller CD.

The Binding of Different Substrate Molecules at the Docking Site and the Active Site of γ-Secretase Can Trigger Toxic Events in Sporadic and Familial Alzheimer's Disease.

Pathogenic changes in γ-secretase activity, along with its response to different drugs, can be affected by changes in the saturation of γ-secretase with its substrate. We analyze the saturation of γ-secretase with its substrate using multiscale molecular dynamics studies. We found that an increase in the saturation of γ-secretase with its substrate could result in the parallel binding of different substrate molecules at the docking site and the active site. The C-terminal domain of the substrate bound at the docking site can interact with the most dynamic presenilin sites at the cytosolic end of the active site tunnel. Such interactions can inhibit the ongoing catalytic activity and increase the production of the longer, more hydrophobic, and more toxic Aß proteins. Similar disruptions in dynamic presenilin structures can be observed with different drugs and disease-causing mutations. Both, C99-ßCTF-APP substrate and its different Aß products, can support the toxic aggregation. The aggregation depends on the substrate N-terminal domain. Thus, the C99-ßCTF-APP substrate and ß-secretase path can be more toxic than the C83-αCTF-APP substrate and α-secretase path. Nicastrin can control the toxic aggregation in the closed conformation. The binding of the C99-ßCTF-APP substrate to γ-secretase can be controlled by substrate channeling between the nicastrin and ß-secretase. We conclude that the presented two-substrate mechanism could explain the pathogenic changes in γ-secretase activity and Aß metabolism in different sporadic and familial cases of Alzheimer's disease. Future drug-development efforts should target different cellular mechanisms that regulate the optimal balance between γ-secretase activity and amyloid metabolism.

Rheo-SAXS characterization of lead-treated oils: Understanding the influence of lead driers on artistic oil paint's flow properties.

From the 15th century onwards, painters began to treat their oils with lead compounds before grinding them with pigments. Such a treatment induces the partial hydrolysis of the oil triglycerides and the formation of lead soaps, which significantly modify the rheological properties of the oil paint. Organization at the supramolecular scale is thus expected to explain these macroscopic changes. Synchrotron Rheo-SAXS (Small Angle X-ray Scattering) measurements were carried out on lead-treated oils, with different lead contents. We can now propose a full picture of the relationship between structure and rheological properties of historical saponified oils. At rest, lead soaps in oil are organized as lamellar phases with a characteristic period of 50 Å. Under shear, the loss of viscoelastic properties can be linked to the modification of this organization. Continuous shear resulted in a preferential and reversible orientation of the lamellar domains which increased with the concentration of lead soaps. The parallel orientation predominates over the entire shear range (0-1000 s-1). Conversely, oscillatory shear coiled the lamellae into cylinders that oriented themselves vertically in the rheometer cell. This is the first report of such a vertical cylindrical structure obtained under shear from lamellae.

Crystalline State Determines the Potency of Galectin-10 Protein Assembly to Induce Inflammation.

Protein crystallization is a prevalent phenomenon existing in the formation of intricate protein-assembled structures in living cells. Whether the crystallization of a protein would exert a specific biological function, however, remains poorly understood. Here, we reconstructed a recombinant galectin-10 (gal-10) protein and artificially engineered a gal-10 protein assembly in two distinguishable states: i.e., an insoluble crystalline state and a soluble state. The potency of the gal-10 protein in either the crystalline state or the soluble state to induce chemokine or cytokine release in the primary human nasal epithelial cells and nasal polyps derived from chronic rhinosinusitis patients with nasal polyps was investigated. The crystalline gal-10 upregulated the gene expression of chemokines or cytokines, including IL-1ß, IL-6, IL-8, TNF-α, and GM-CSF, in patient-derived primary cells and nasal polyps. In contrast, soluble gal-10 displayed a diminished potency to induce inflammation. Our results demonstrate that the gal-10 protein potency of activating inflammation is correlated with its crystalline state.

The Impact of Tyrosine Iodination on the Aggregation and Cleavage Kinetics of MMP-9-Responsive Peptide Sequences.

Matrix metalloproteinase (MMP) enzymes are over-expressed by some metastatic cancers, in which they are responsible for the degradation and remodeling of the extracellular matrix. In recent years, MMPs have emerged as promising targets for enzyme-responsive diagnostic probes because oligopeptides can be designed to be selectively hydrolyzed by exposure to these enzymes. With the ultimate goal of developing radio-iodinated peptides as supramolecular building blocks for MMP-sensitive tools for nuclear imaging and therapy, we designed three MMP-9-responsive peptides containing either tyrosine or iodotyrosine to assess the impact of iodotyrosine introduction to the peptide structure and cleavage kinetics. We found that the peptides containing iodotyrosine underwent more rapid and more complete hydrolysis by MMP-9. While the peptides under investigation were predominantly disordered, it was found that iodination increased the degree of aromatic residue-driven aggregation of the peptides. We determined that these iodination-related trends stem from the improved overall intramolecular order through H- and halogen bonding, in addition to intermolecular organization of the self-assembled peptides due to steric and electrostatic effects introduced by the halogenated tyrosine. These fundamental observations provide insights for the development of enzyme-triggered peptide aggregation tools for localized radioactive iodine-based tumor imaging.

Supramolecular organization of Cytochrome-C into quantum-dot decorated macromolecular network under pH and thermal stress.

The holo form of Cytochrome-C which is involved in the electron transfer chain of aerobic and anaerobic respiration remains structurally intact by its complex with heme. However, when a prolonged thermal and pH stress was applied, heme was found to abruptly dissociate from the holo protein, resulting in complete collapse of the three-dimensional functional structure. Interestingly, two distinct structures were formed as the consequence of the dissociation event: (i) A macromolecular amyloid-network formed by the collapsed protein fragments, generated by self-oxidation, and (ii) Fe-containing Quantum-Dots (FeQDs) with 2-3 nm diameter formed by heme reorganization. Further adding to intrigue, the FeQDs were re-adsorbed on the surface of the amyloid network leading to FeQD-decorated macromolecular amyloid matrix. The heme-interactant Met80, constituting the amyloidogenic region, initiates the amylogenic cascade, and gradual exposure of Trp59 synergistically emit intrinsic fluorescence alongside FeQDs. The development of the aforementioned events were probed through a multitude of biophysical, chemical and computational analyses like ThT/ANS/intrinsic fluorescence assays, CD-spectroscopy, FETEM/STEM/elemental mapping, Foldamyloid/Foldunfold/Isunstruct/H-protection/LIGplot analyses, etc. The FeQD-decorated amyloid-network was found to exhibit gel-like property, which supported the growth of BHK-21 fibroblast without cytotoxicity. Further studies on FeQD-decorated Cytochrome C amyloid network might open possibilities to design advanced biomaterial for diverse biological applications.

The Effect of Alkyl Substitution of Novel Imines on Their Supramolecular Organization, towards Photovoltaic Applications.

Three novel conjugated polyazomethines have been obtained by polycondensation of diamines consisting of the diimine system, with either 2,5-bis(octyloxy)terephthalaldehyde or 9-(2-ethylhexyl)carbazole-3,6-dicarboxaldehyde. Partial replacement of bulky solubilizing substituents with the smaller side groups has allowed to investigate the effect of supramolecular organization. All obtained compounds have been subsequently identified using the NMR and FTIR spectroscopies and characterized by the thermogravimetric analysis, differential scanning calorimetry, cyclic voltammetry, UV-Vis spectroscopy, and X-ray diffraction. Investigated polymers have shown a good thermal stability and high glass transition temperatures. X-ray measurements have proven that partial replacement of octyloxy side chains with smaller methoxy groups induced a better planarization of macromolecule. Such modification has tuned the LUMO level of this molecule and caused a bathochromic shift of the lowest energy absorption band. On the contrary, imines consisting of N-ethylhexyl substituted carbazole units have not been so clearly affected by alkyl chain length modification. Photovoltaic activity of imines (acting as a donor) in bulk-heterojunction systems has been observed for almost all studied compounds, blended with the fullerene derivative (PCBM) in various weight ratios.