Search Results (149)

Retroviruses are single-stranded RNA viruses that package two copies of their positively stranded RNA genomes as a non-covalent dimer into newly formed virions. This process is evolutionarily conserved, and disruption of genome dimerization results in production of non-infectious virus particles. Genome dimers can be packaged as homodimers, containing two identical RNAs, or heterodimers, consisting of two genetically distinct copies. Genome dimerization generates genetic diversity, and different retroviruses have preferences for the type of genome dimers packaged into virions. We developed a novel imaging approach to specifically label and detect retroviral genome heterodimers in cells using a modified bimolecular fluorescence complementation (BiFC) technique. This method utilizes viral genomes encoding two different RNA stem-loop cassettes that each specifically binds to an RNA-binding protein conjugated to a split fluorophore. When two genetically different genomes are within close proximity, the fluorophore halves come together to reconstitute fluorescence. These BiFC-labeled RNA dimers can be visualized and tracked in living cells and interact with retroviral Gag proteins. This method has the advantage of low background fluorescence and can be applied to the study of dimeric or double-stranded RNAs of viruses and other organisms. Full article

Chrysanthemum species represent an economically important group of flowering plants. Many species also present a medicinal interest, notably for the treatment of inflammatory pathologies. This is the case for Chrysanthemum boreale Makino, endemic to Japan and widespread in Eastern Asia. This perennial plant has long been used in folk medicine to treat inflammatory diseases and bacterial infections. An extensive review of the scientific literature pertaining to C. boreale has been performed to analyze the origin of the plant, its genetic traits, the traditional usages, and the properties of aqueous or organic plant extracts and essential oils derived from this species. Aqueous extracts and the associated flavonoids, such as acacetin and glycoside derivatives, display potent antioxidant activities. These aqueous extracts and floral waters are used mainly as cytoprotective agents. Organic extracts, in particular those made from methanol or ethanol, essentially display antioxidant and anti-inflammatory properties useful to protect organs from oxidative damage. They can be used for neuroprotection. Essential oils from C. boreale have been used as cytoprotective or antibacterial agents. The main bioactive natural products isolated from the plant include flavonoids such as acacetin and related glycosides (notably linarin), and diverse sesquiterpene lactones (SLs). Among monomeric SLs, cumambrins and borenolide are the main products of interest, with cumambrin A targeting covalently the transcription factor NF-κB to regulate proinflammatory gene expression to limit osteoclastic bone resorption. The dimeric SL handelin, which is characteristic of C. boreale, exhibits a prominent anti-inflammatory action, with a capacity to target key proteins like kinase TAK1 and chaperone Hsp70. A few other natural products isolated from the plant (tulipinolide, polyacetylenic derivatives) are discussed. Altogether, the review explores all medicinal usages of the plant and the associated phytochemical panorama, with the objective of promoting further botanical and chemical studies of this ancestral medicinal species. Full article

The organic multi-chromophore system has been increasingly attractive due to the potential optoelectronic applications. The inter-chromophore electronic coupling (EC), i.e., J_Coul and J_CT, plays a critical role in determining the relaxation path of the excited state. However, the molecular designing strategy for effective tuning of inter-chromophore EC is still challenging. In this computational work, we designed a series of perylene diimides (PDI) covalent dimers with rigid linking cores containing thiophene (Th) or phenyl (Ph) fragments and performed corresponding theoretical investigation to analyze the inter-PDI electronic coupling. Vibrational analysis indicated that the minimized excited state structural relaxation (ES-SR) can ensure the rigid inter-PDI geometry pre-defined by the topological characteristic of linking cores, leading to comparable |J_Coul| on S₀ and S₁ states. The saddle-shaped linking cores allow collaborative tuning of inter-PDI dihedral (α) and slipping (θ) angles, leading to effective tuning of inter-PDI |J_Coul| = 0–1000 cm⁻¹. Our work provides a new molecular designing strategy for effective tuning of inter-chromophore EC for organic chromophores. By using a rigid inter-chromophore structure, the ignorable ES-SR allows simplified molecular designing without considering the plausible geometric difference between S₁ and S₀ states, which might be useful for future applications in organic optoelectronics. Full article

Silicon–lithium clusters are promising candidates for hydrogen storage due to their lightweight composition, high gravimetric capacities, and favorable non-covalent binding characteristics. In this study, we employ density functional theory (DFT), global optimization (AUTOMATON and Kick–MEP), and Born–Oppenheimer molecular dynamics (BOMD) simulations to evaluate the structural stability and hydrogen storage performance of key Li–Si systems. The exploration of their potential energy surface (PES) reveals that the true global minima of Li₆Si₆ and Li₁₀Si₁₀ differ markedly from those of the earlier Si–Li structures proposed as structural analogs of aromatic hydrocarbons such as benzene and naphthalene. Instead, these clusters adopt compact geometries composed of one or two Si₄ (T_d) units and a Si₂ dimer, all stabilized by surrounding Li atoms. Motivated by the recurrence of the Si₄–T_d motif, we explore oligomers of Li₄Si₄, which can be viewed as electronically transmuted analogues of P₄, confirming the additive H₂ uptake across dimer, trimer, and tetramer assemblies. Within the series of Si–Li clusters evaluated, the Li₁₂Si₅ sandwich complex, featuring a σ-aromatic Si₅¹⁰⁻ ring encapsulated by two Li₆⁵⁺ moieties, achieves the highest hydrogen capacity, adsorbing 34 H₂ molecules with a gravimetric density of 23.45 wt%. Its enhanced performance arises from the high density of accessible Li⁺ adsorption sites and the electronic stabilization afforded by delocalized σ-bonding. BOMD simulations at 300 and 400 K confirm their dynamic stability and reversible storage behavior, while analysis of the interaction regions confirms that hydrogen adsorption proceeds via weak, dispersion-driven physisorption. These findings clarify the structure–property relationships in Si–Li clusters and provide a basis for designing modular, lightweight, and thermally stable hydrogen storage materials. Full article

Based on first-principles calculations, the stability of three adsorption configurations of glycine on the (100) surface of diamonds was studied, leading to an investigation into the surface-enhanced Raman scattering (SERS) effect of the diamond substrate. The results showed that the carboxyl-terminated adsorption configuration (CAR) was the most stable and shortest interface distance compared to other configurations. This stability was primarily attributed to the formation of strong polar covalent bonds between the carboxyl O atoms and the surface C atoms of the (100) surface of diamonds. These results were further corroborated by first-principles molecular dynamics simulations. Within the temperature range of 300 to 500 K, the glycine molecules in the carboxyl-terminated adjacent-dimer phenyl-like (CAR) configuration exhibited only simple thermal vibrations with varying amplitudes. In contrast, the metastable ATO and carboxyl-terminated trans-dimer phenyl-like ring (CTR) configurations were observed to gradually transform into benzene-ring-like structures akin to the CAR configuration. After adsorption, the intensity of glycine’s characteristic peaks increased substantially, accompanied by a blue shift phenomenon. Notably, the characteristic peaks related to the carboxyl and amino groups exhibited the highest enhancement amplitude, exceeding 200 times, with an average enhancement amplitude exceeding 50 times. The diamond substrate, with its excellent adsorption properties and strong surface Raman spectroscopy characteristics, represents a highly promising candidate in the field of biomedicine. Full article

Synthesis of para-carboxyhydrazinylidene, the derivative of 3-nitrophenylthiazolo[3,2-a]pyrimidine, was successfully performed with good yields. It was established that different types of non-covalent intermolecular interaction may influence the supramolecular motif-synthesized compound. Hydrogen- and chalcogen-bonding supramolecular driving forces collectively impacted the results of two types of the centrosymmetric racemic dimeric self-assembly in crystalline phase. Full article

This work is devoted to the synthesis of triazolyl derivatives based on propargyl ethers of the thiazolo[3,2-a]pyrimidine series by [3+2]-cycloaddition and the study of their structure in solution and crystalline phase. The formation of homochiral chains in the crystalline phase is attributed to the establishment of a halogen bond between the bromine atom and the nitrogen atom of the nitrile group. Additionally, the generation of a racemic dimer is linked to the formation of a halogen bond between the bromine atom and the nitrogen atom of the triazolyl fragment. Full article

The pathogen of COVID-19, SARS-CoV-2, has caused a severe global health crisis. So far, while COVID-19 has been suppressed, the continuous evolution of SARS-CoV-2 variants has reduced the effectiveness of vaccines such as mRNA-1273 and drugs such as Remdesivir. To uphold the effectiveness of vaccines and drugs prior to potential coronavirus outbreaks, it is necessary to explore the underlying mechanisms between biomolecules and nanodrugs. The experimental study reported that acrylamide fragments covalently attached to Cys145, the main protease enzyme (Mpro) of SARS-CoV-2, and occupied the substrate binding pocket, thereby disrupting protease dimerization. However, the potential mechanism linking them is unclear. The purpose of this work is to complement and validate experimental results, as well as to facilitate the study of novel antiviral drugs. Based on our experimental studies, we identified two acrylamide fragments and constructed corresponding protein-ligand complex models. Subsequently, we performed molecular dynamics (MD) simulations to unveil the crucial interaction mechanisms between these nanodrugs and SARS-CoV-2 Mpro. This approach allowed the capture of various binding conformations of the fragments on both monomeric and dimeric Mpro, revealing significant conformational dissociation between the catalytic and helix domains, which indicates the presence of allosteric targets. Notably, Compound 5 destabilizes Mpro dimerization and acts as an effective inhibitor by specifically targeting the active site, resulting in enhanced inhibitory effects. Consequently, these fragments can modulate Mpro’s conformational equilibrium among extended monomeric, compact, and dimeric forms, shedding light on the potential of these small molecules as novel inhibitors against coronaviruses. Overall, this research contributes to a broader understanding of drug development and fragment-based approaches in antiviral covalent therapeutics. Full article

The supramolecular structure of the crystal products–N-[2-chloro-2-(silatranyl)ethyl]-4-nitro-benzenesulfonamide 4d and N-chloro-N-[2-chloro-1-(silatran-1-yl-methyl)ethyl]benzene-sulfonamide 5a was established by X-ray diffraction analysis data, FTIR spectroscopy and DFT quantum chemical calculations. Their crystal lattice is formed by cyclic dimers with intermolecular hydrogen NH∙∙∙O-Si bonds and CH∙∙∙O=S short contacts. The distribution of electron density in the monomers was determined using quantum chemical calculations of their molecular electrostatic potential (MESP) in an isolated state (in gas) and in a polar medium. The transition from covalent N–Si bonds in crystal compounds and polar medium to non-covalent N∙∙∙Si bonds happened while performing the calculations on the monomer molecules and their dimers in gas. The effect of intermolecular interactions on the strength of the N–Si and N∙∙∙Si bonds in molecules was evaluated through calculations of their complexes with H₂O and DMSO. Full article

Oligo(phenylene ethynylene)s (OPEs) are π-conjugated systems with promising optical, bioactive, and electrical properties, making them valuable candidates for molecular electronics and biosensors. Controlling the arrangement and orientation of π-conjugated systems is crucial in developing molecular devices. Recently, we developed insulated diarylacetylene dimers using a [c2]daisy chain rotaxane strategy, which brings two cores into close proximity without covalent bonding and shields them with permethylated α-cyclodextrins. Here, we synthesized an insulated OPE dimer using a similar rotaxane strategy to investigate its optical properties. The rotaxane structure and optical properties were evaluated using nuclear magnetic resonance (NMR) spectroscopy, electrospray ionization high-resolution mass spectrometry (ESI-HRMS), and absorption and fluorescence spectroscopy. This study is expected to contribute to the development of optical and electronic materials utilizing OPEs. Full article

This research aimed to evaluate the gelation process of ferulated pectin (FP) and ferulated arabinoxylan (AXF) in a new mixed hydrogel and determine its microstructural characteristics. FP from sugar beet (Beta vulgaris) and arabinoxylan from maize (Zea mays) bran were gelled via oxidative coupling using laccase as a crosslinking agent. The dynamic oscillatory rheology of the mixed hydrogel revealed a maximum storage modulus of 768 Pa after 60 min. The scanning electron microscopy images showed that mixed hydrogels possess a microstructure of imperfect honeycomb. The ferulic acid content of the mixed hydrogel was 3.73 mg/g, and ferulic acid dimer 8-5′ was the most abundant. The presence of a trimer was also detected. This study reports the distribution and concentration of ferulic acid dimers, and the rheological and microstructural properties of a mixed hydrogel based on FP and AXF, which has promising features as a new covalent biopolymeric material. Full article

The condensation reactions of 4,4′-(ethane-1,2-diylbis (oxy)) bis(3-methoxybenzaldehyde) (VV) with cystamine, 1,6-hexamenthylene diamine, and a dimer diamine (Priamine^TM 1075) produced three types of vanillin-derived imine-and disulfide-containing diamines (VC, VH, and VD, respectively). Thermal curing reactions of polyglycerol polyglycidyl ether with VD and mixtures of VC/VD and VH/VD produced bio-based epoxy vitrimers (BEV-VD, BEV-VC/VD, and BEV-VH/VD, respectively). The degree of swelling and gel fraction tests revealed the formation of a network structure, and the crosslinking density increased with a decreasing VD fraction. The glass transition temperature, tensile strength, and tensile modulus of the cured films increased as the VD fraction decreased. In contrast, the thermal degradation temperature of the cured films increased as the VD fraction increased. All the cured films were healed by hot pressing at 120 °C for 2 h under 1 MPa at least three times. The healing efficiencies, based on tensile strength after the first healing treatment, were 75–78%, which gradually decreased as the healing cycle was repeated. When imine-and disulfide-containing BEV-VC/VD and imine-containing BEV-VH/VD with the same VC/VD and VH/VD ratios were used, the former exhibited a slightly higher healing efficiency. Full article

The conservation of the main protease in viral genomes, combined with the absence of a homologous protease in humans, makes this enzyme family an ideal target for developing broad-spectrum antiviral drugs with minimized host toxicity. GC-376, a peptidomimetic 3CL protease inhibitor, has shown significant efficacy against coronaviruses. Recently, a GC-376-based PROTAC was developed to target and induce the proteasome-mediated degradation of the dimeric SARS-CoV-2 3CL^Pro protein. Extending this approach, the current study investigates the application of the GC-376 PROTAC to the 3C^Pro protease of enteroviruses, specifically characterizing its interaction with CVB3 3C^Pro through X-ray crystallography, NMR (Nuclear Magnetic Resonance) and biochemical techniques. The crystal structure of CVB3 3C^Pro bound to the GC-376 PROTAC precursor was obtained at 1.9 Å resolution. The crystallographic data show that there are some changes between the binding of CVB3 3C^Pro and SARS-CoV-2 3CL^Pro, but the overall similarity is strong (RMSD on C-alpha 0.3 Å). The most notable variation is the orientation of the benzyloxycarbonyl group of GC-376 with the S4 subsite of the proteases. NMR backbone assignment of CVB3 3C^Pro bound and unbound to the GC-376 PROTAC precursor (80% and 97%, respectively) was obtained. This information complemented the investigation, by NMR, of the interaction of CVB3 3C^Pro with the GC-376 PROTAC, and its precursor allows us to define that the GC-376 PROTAC binds to CVB3 3C^Pro in a mode very similar to that of the precursor. The NMR relaxation data indicate that a quench of dynamics of a large part of the protein backbone involving the substrate-binding site and surrounding regions occurs upon GC-376 PROTAC precursor binding. This suggests that the substrate cavity, by sampling different backbone conformations in the absence of the substrate, is able to select the suitable one necessary to covalently bind the substrate, this being the latter reaction, which is the fundamental step required to functionally activate the enzymatic reaction. The inhibition activity assay showed inhibition potency in the micromolar range for GC-376 PROTAC and its precursor. Overall, we can conclude that the GC-376 PROTAC fits well within the binding sites of both proteases, demonstrating its potential as a broad-spectrum antiviral agent. Full article

An H-bond involves the sharing of a hydrogen atom between an electronegative atom to which it is covalently bound (the donor) and another electronegative atom serving as an acceptor. Such bonds represent a critically important geometrical force in biological macromolecules and, as such, have been characterized extensively. H-bond formation invariably leads to a weakening within the acceptor moiety due to the pulling exerted by the donor hydrogen. This phenomenon can be compared to a spring connecting two masses; pulling one mass stretches the spring, similarly affecting the bond between the two masses. Herein, we describe the opposite phenomenon when investigating the energetics of the C–H···O=C bond. This bond underpins the most prevalent protein transmembrane dimerization motif (GxxxG) in which a glycine Cα-H on one helix forms a hydrogen bond with a carbonyl in a nearby helix. We use isotope-edited FT-IR spectroscopy and corroborating computational approaches to demonstrate a surprising strengthening of the acceptor C=O bond upon binding with the glycine Cα-H. We show that electronic factors associated with the Cα-H bond strengthen the C=O oscillator by increasing the s-character of the σ-bond, lowering the hyperconjugative disruption of the π-bond. In addition, a reduction of the acceptor C=O bond’s polarity is observed upon the formation of the C–H···O=C bond. Our findings challenge the conventional understanding of H-bond dynamics and provide new insights into the structural stability of inter-helical protein interactions. Full article

Neuroblastoma (NB) is a cancer of the peripheral nervous system found in children under 15 years of age. It is the most frequently diagnosed cancer during infancy, accounting for ~12% of all cancer-related deaths in children. Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a membrane receptor that is associated with the primary tumor formation and metastasis of cancers in the gastrointestinal system. Remarkably, high levels of LGR5 are found in NB tumor cells, and high LGR5 expression is strongly correlated with poor survival. Antibody–drug conjugates (ADCs) are monoclonal antibodies that are covalently linked to cell-killing cytotoxins to deliver the payloads into cancer cells. We generated an ADC with an anti-LGR5 antibody and pyrrolobenzodiazepine (PBD) dimer-based payload SG3199 using a chemoenzymatic conjugation method. The resulting anti-LGR5 ADC was able to inhibit the growth of NB cells expressing LGR5 with high potency and specificity. Importantly, the ADC was able to completely inhibit the growth of NB xenograft tumors in vivo at a clinically relevant dose for the PBD class of ADCs. The findings support the potential of targeting LGR5 using the PBD class of payload for the treatment of high-risk NBs. Full article