Reaction of a Programmable Glycan Presentation of Glycodendrimersomes and Cells with Engineered Human Lectins To Show the Sugar Functionality of the Cell Surface

Chemical and biological tools are harnessed to investigate the impact of spatial factors for functional pairing of human lectins with counterreceptors. The homodimeric adhesion/growth‐regulatory galectin‐1 and a set of covalently linked homo‐oligomers from di‐ to tetramers serve as proof‐of‐principle test cases. Glycodendrimersomes provide a versatile and sensitive diagnostic platform to reveal thresholds for ligand density and protein concentration in aggregation assays (trans ‐activity), irrespective of linker length between lectin domains. Monitoring the affinity of cell binding and ensuing tumor growth inhibition reveal the linker length to be a bidirectional switch for cis ‐activity. The discovery that two aspects of lectin functionality (trans ‐ versus cis ‐activity) respond non‐uniformly to a structural change underscores the power of combining synthetic and biological tools to advance understanding of the sugar functionality of the cell surface.     

Mimicking Biological Membranes with Programmable Glycan Ligands Self‐Assembled from Amphiphilic Janus Glycodendrimers

An accelerated modular synthesis produced 18 amphiphilic Janus glycodendrimers with three different topologies formed from either two or one carbohydrate head groups or a mixed constellation with a noncarbohydrate hydrophilic arm. By simple injection of their THF solutions into water or buffer, all of the Janus compounds self‐assembled into uniform, stable, and soft unilamellar vesicles, denoted glycodendrimersomes. The mixed constellation topology glycodendrimersomes were demonstrated to be most efficient in binding plant, bacterial, and human lectins. This evidence with biomedically relevant receptors offers a promising perspective for the application of such glycodendrimersomes in targeted drug delivery, vaccines, and other areas of nanomedicine.     

Structural Characterization of N-Linked Glycans in the Receptor Binding Domain of the SARS-CoV-2 Spike Protein and their Interactions with Human Lectins

The glycan structures of the receptor binding domain of the SARS-CoV2 spike glycoprotein expressed in human HEK293F cells have been studied by using NMR. The different possible interacting epitopes have been deeply analysed and characterized, providing evidence of the presence of glycan structures not found in previous MS-based analyses. The interaction of the RBD ¹³C-labelled glycans with different human lectins, which are expressed in different organs and tissues that may be affected during the infection process, has also been evaluated by NMR. In particular, ¹⁵N-labelled galectins (galectins-3, -7 and -8 N-terminal), Siglecs (Siglec-8, Siglec-10), and C-type lectins (DC-SIGN, MGL) have been employed. Complementary experiments from the glycoprotein perspective or from the lectin's point of view have permitted to disentangle the specific interacting epitopes in each case. Based on these findings, 3D models of the interacting complexes have been proposed.     

Thiol‐alkyne Chemistry for the Preparation of Micelles with Glycopolymer Corona: Dendritic Surfaces versus Linear Glycopolymer in Their Ability to Bind to Lectins

A poly(tert‐butyl acrylate) (P(tBA)) with a glycodendric endfunctionality with eight glucose moieties was synthesised in four steps via a combination of esterification, thiol‐alkyne conjugation and hetero‐Diels–Alder (HDA) cycloaddition. A linear glycopolymer of similar size and composition was also synthesised in order to compare the protein binding characteristics of the polymer with glycodendritic endfunctionality to the linear glycol blockcopolymer. The two amphiphilic polymers were self‐assembled in water into micelles. These particles were then tested for their ability to bind to Concanavalin A (Con A). In a turbidity assay, the polymer glycodendron exhibited a significantly faster clustering rate to the lectin as compared to the linear glycopolymer. In a precipitation assay, it is found that significantly less glucose residue is required for binding per Con A for the polymer with the glycodendritic endfunctionality.

     

Interactions between Human Serum Albumin and Sulfadimethoxine Determined Using Spectroscopy and Molecular Docking

Sulfonamides are widely used antibiotics in agricultural production. However, the potential threat of these drugs to human health has increased global concern. Human serum albumin (HSA) is the main reservoir and transporter of exogenous small molecules in humans. In this study, the interaction between sulfadimethoxine (SMT) and human serum albumin (HSA) was studied using spectroscopy and computer simulation. Our results showed that the hydrogen bonding and van der Waals forces drove SMT to enter the binding site I of HSA spontaneously and resulted in the fluorescence quenching of HSA. The stability of the HSA–SMT complex decreased with an increase in temperature. The binding of SMT to HSA induced alterations in the secondary structure of HSA, where the content of α-helix decreased from 61.0% of the free state to 59.0% of the compound state. The π–π, π–σ, and π–alkyl interactions between HSA and SMT were found to play important roles in maintaining the stability of the complex.     

多溴联苯醚与人血清白蛋白相互作用的表面等离子体共振及分子对接

采用表面等离子体共振(SPR)技术,在模拟生理条件下实时动态研究了8种典型多溴联苯醚(PBDEs)与人血清白蛋白(HSA)相互作用的动力学和热力学行为.通过分子对接模拟研究了PBDEs与HSA相互作用的分子机制,探讨了不同PBDEs与蛋白的结合模式及作用力.动力学实验结果表明, PBDEs中溴原子的个数和取代位置对相互作用有规律性的影响.溴原子通过改变PBDEs分子与HSA作用过程中的解离速率来影响其亲和力,溴原子个数越多, PBDEs与HSA作用的亲和力越强;而取代基位置则影响PBDEs与HSA作用结合速率的快慢,同分异构体中间位取代溴的亲和力大于邻位取代溴.分子对接结果显示, 8种PBDEs主要结合于HSA的Site I位点,但结合位点周边氨基酸残基类型的差异影响了结合力.范德华力和氢键对结合能的贡献远大于静电力.     

Molecular Interactions and Thermodynamic Aspects of the Complexation Reaction between Gentian Violet and Several Cyclodextrins

The complexation process between gentian violet (CV+) and four different cyclodextrins (-, -, -, and HP--CDs) has been investigated under different reaction conditions (pH, solvent, and temperature) by electronic absorption and 1H NMR (NOE and NOESY) spectroscopies. All the binding constants were determined by the direct spectroscopic method. The H and S complexation values have been evaluated and discussed according to the diverse factors that affect the chemical interactions in these systems. A simple association takes place between the secondary hydroxyl or the hydroxypropyl groups of and HP--cycloamyloses, respectively, with the amine group of the gentian violet, while the binding between CV+ and - or -CDs corresponds to a real inclusion. Also, a CV22+ dimmeric species within the -CD cavity was detected in aqueous solution, while two molecules of -CD react with one molecule of gentian violet in DMSO at 294 K. In all the reaction media the -CD forms 1 : 1 complexes, but in the buffered aqueous solution at pH 7.5 the inclusion is deeper than in the other solvents. It is important to point out that the solvophobic effect is the most important binding factor in the complexation of the CV+ with the - and HP--CDs, while the complexes with -, and -cyclodextrins are mainly stabilized by van der Waals interactions between the guest and the host cavity. In all cases, the inclusion orientation is probably determined by the ion-dipole interactions between gentian violet and the solvent.     

Structural Prediction and Characterization of Canavalia grandiflora (ConGF) Lectin Complexed with MMP1: Unveiling the Antiglioma Potential of Legume Lectins

A glioblastoma (GBM) is a highly malignant primary brain tumor with a poor prognosis because of its invasiveness and high resistance to current therapies. In GBMs, abnormal glycosylation patterns are associated with malignancy, which allows for the use of lectins as tools for recognition and therapy. More specifically, lectins can interact with glycan structures found on the malignant cell surface. In this context, the present work aimed to investigate the antiglioma potential of ConGF, a lectin purified from Canavalia grandiflora seeds, against C6 cells. The treatment of C6 cells with ConGF impaired the mitochondrial transmembrane potential, reduced cell viability, and induced morphological changes. ConGF also induced massive autophagy, as evaluated by acridine orange (AO) staining and LC3AB-II expression, but without prominent propidium iodide (PI) labeling. The mechanism of action appears to involve the carbohydrate-binding capacity of ConGF, and in silico studies suggested that the lectin can interact with the glycan structures of matrix metalloproteinase 1 (MMP1), a prominent protein found in malignant cells, likely explaining the observed effects.     

Interactions and Encapsulation of Vitamins C,B3, and B6 with Dendrimers in Water

Titrations of commercial diaminobutane (DAB) and polyamidoamine (PAMAM) dendrimers by vitamins C (ascorbic acid, AA), B₃ (nicotinic acid), and B₆ (pyridoxine) were monitored by ¹H NMR spectroscopy using the chemical shifts of both dendrimer and vitamin protons and analyzed by comparison with the titration of propylamine. Quaternarizations of the terminal primary amino groups and intradendritic tertiary amino groups, which are nearly quantitative with vitamin C, were characterized by more or less sharp variations (Δδ) of the ¹H chemical shift (δ) at the equivalence points. The peripheral primary amino groups of the DAB dendrimers were quaternarized first, but not selectively, whereas a sharp chemical‐shift variation was recorded for the inner methylene protons near the tertiary amines, thereby indicating encapsulation, when all the dendritic amines were quaternarized. With DAB‐G5‐64‐NH₂, some excess acid is required to protonate the inner amino groups, presumably because of basicity decrease due to excess charge repulsion. On the other hand, this selectivity was not observed with PAMAM dendrimers. The special case of the titration of the dendrimers by vitamin B₆ indicates only dominant supramolecular hydrogen‐bonding interactions and no quaternarization, with core amino groups being privileged, which indicates the strong tendency to encapsulate vitamins. With vitamin B₃, a carboxylic acid, titration of DAB‐G3‐16‐NH₂ shows that only six peripheral amino groups are protonated on average, even with excess vitamin B₃, because protonation is all the more difficult due to increased charge repulsion, as positive charges accumulate around the dendrimer. Inner amino groups interact with this vitamin, however, thus indicating encapsulation presumably with supramolecular hydrogen bonding without much charge transfer.     

A Comprehensive Investigation of Interactions between Antipsychotic Drug Quetiapine and Human Serum Albumin Using Multi-Spectroscopic,Biochemical, and Molecular Modeling Approaches

Quetiapine (QTP) is a short-acting atypical antipsychotic drug that treats schizophrenia or manic episodes of bipolar disorder. Human serum albumin (HSA) is an essential transport protein that transports hormones and various other ligands to their intended site of action. The interactions of QTP with HSA and their binding mechanism in the HSA-QTP system was studied using spectroscopic and molecular docking techniques. The UV-Vis absorption study shows hyperchromicity in the spectra of HSA on the addition of QTP, suggesting the complex formation and interactions between QTP and HSA. The results of intrinsic fluorescence indicate that QTP quenched the fluorescence of HSA and confirmed the complex formation between HSA and QTP, and this quenching mechanism was a static one. Thermodynamic analysis of the HSA-QTP system confirms the involvement of hydrophobic forces, and this complex formation is spontaneous. The competitive displacement and molecular docking experiments demonstrated that QTP is preferentially bound to HSA subdomain IB. Furthermore, the CD experiment results showed conformational changes in the HSA-QTP system. Besides this, the addition of QTP does not affect the esterase-like activity of HSA. This study will help further understand the credible mechanism of transport and delivery of QTP via HSA and design new QTP-based derivatives with greater efficacy.     

Molecular Dynamics Simulations Study of the Interactions between Human Dipeptidyl-Peptidase III and Two Substrates

Human dipeptidyl-peptidase III (hDPP III) is capable of specifically cleaving dipeptides from the N-terminal of small peptides with biological activity such as angiotensin II (Ang II, DRVYIHPF), and participates in blood pressure regulation, pain modulation, and the development of cancers in human biological activities. In this study, 500 ns molecular dynamics simulations were performed on free-hDPP III (PDB code: 5E33), hDPP III-Ang II (PDB code: 5E2Q), and hDPP III-IVYPW (PDB code: 5E3C) to explore how these two peptides affect the catalytic efficiency of enzymes in terms of the binding mode and the conformational changes. Our results indicate that in the case of the hDPP III-Ang II complex, subsite S1 became small and hydrophobic, which might be propitious for the nucleophile to attack the substrate. The structures of the most stable conformations of the three systems revealed that Arg421-Lys423 could form an α-helix with the presence of Ang II, but only part of the α-helix was produced in hDPP III-IVYPW. As the hinge structure in hDPP III, the conformational changes that took place in the Arg421-Lys423 residue could lead to the changes in the shape and space of the catalytic subsites, which might allow water to function as a nucleophile to attack the substrate. Our results may provide new clues to enable the design of new inhibitors for hDPP III in the future.     

The Cooperative Effect of Both Molecular and Supramolecular Chirality on Cell Adhesion

Although helical nanofibrous structures have great influence on cell adhesion, the role played by chiral molecules in these structures on cells behavior has usually been ignored. The chirality of helical nanofibers is inverted by the odd–even effect of methylene units from homochiral l ‐phenylalanine derivative during assembly. An increase in cell adhesion on left‐handed nanofibers and weak influence of cell behaviors on right‐handed nanofibers are observed, even though both were derived from l ‐phenylalanine derivatives. Weak and negative influences on cell behavior was also observed for left‐ and right‐handed nanofibers derived from d ‐phenylalanine, respectively. The effect on cell adhesion of single chiral molecules and helical nanofibers may be mutually offset.     

Interactions of hydrosiloxane and vinylsiloxane groups with aluminum oxide surfaces

Silicone-based materials often contain vinylsiloxane and hydrosiloxane groups for cross-linking by a radical or addition reaction. Such functional groups can influence the interactions with fillers or with surfaces of substrates when used as adhesives. This work examined how these functional groups interact with aluminum oxide surfaces. For this purpose, aluminum oxide powders with large surface areas of 150 m²/g and different acid-base properties were examined. Siloxanes were applied as thin layers to mainly obtain information from the interphase by vibrational spectroscopy. It was observed that vinyl groups show low interactions with aluminum oxide surfaces even at elevated temperatures. In contrast to this, hydrosiloxanes undergo strong interactions and reactions with aluminum oxides already at room temperature. Activated Si─H species were observed as an intermediate state. On the one hand, interactions and reactions might contribute to adhesion, but on the other hand, the cross-linking reaction can be influenced near the surface, leading to lower mechanical strength.     

Resolving Non‐Specific and Specific Adhesive Interactions of Catechols at Solid/Liquid Interfaces at the Molecular Scale

The adhesive system of mussels evolved into a powerful and adaptive system with affinity to a wide range of surfaces. It is widely known that thereby 3,4‐dihydroxyphenylalanine (Dopa) plays a central role. However underlying binding energies remain unknown at the single molecular scale. Here, we use single‐molecule force spectroscopy to estimate binding energies of single catechols with a large range of opposing chemical functionalities. Our data demonstrate significant interactions of Dopa with all functionalities, yet most interactions fall within the medium–strong range of 10–20 k_BT. Only bidentate binding to TiO₂ surfaces exhibits a higher binding energy of 29 k_BT. Our data also demonstrate at the single‐molecule level that oxidized Dopa and amines exhibit interaction energies in the range of covalent bonds, confirming the important role of Dopa for cross‐linking in the bulk mussel adhesive. We anticipate that our approach and data will further advance the understanding of biologic and technologic adhesives.     

Kinetic and Structural Aspects of Glycosaminoglycan–Monkeypox Virus Protein A29 Interactions Using Surface Plasmon Resonance

Monkeypox virus (MPXV), a member of the Orthopoxvirus genus, has begun to spread into many countries worldwide. While the prevalence of monkeypox in Central and Western Africa is well-known, the recent rise in the number of cases spread through intimate personal contact, particularly in the United States, poses a grave international threat. Previous studies have shown that cell-surface heparan sulfate (HS) is important for vaccinia virus (VACV) infection, particularly the binding of VACV A27, which appears to mediate the binding of virus to cellular HS. Some other glycosaminoglycans (GAGs) also bind to proteins on Orthopoxviruses. In this study, by using surface plasmon resonance, we demonstrated that MPXV A29 protein (a homolog of VACV A27) binds to GAGs including heparin and chondroitin sulfate/dermatan sulfate. The negative charges on GAGs are important for GAG–MPXV A29 interaction. GAG analogs, pentosan polysulfate and mucopolysaccharide polysulfate, show strong inhibition of MPXV A29–heparin interaction. A detailed understanding on the molecular interactions involved in this disease should accelerate the development of therapeutics and drugs for the treatment of MPXV.     

Using of Volatile Release Measurements to Understand Polysaccharide Molecular Interactions: An Example with Guar Gum Study

It is well establishment that polysaccharides are commonly used in many fields of formulation such as food and cosmetic industries as viscosity modifiers or gelling agents. Among the different impacts on the mixture properties, these materials are also known to affect the aroma release or retention thus its sensory perception; the effect depends whether polysaccharide structure induces specific retention or release phenomena from the complex media. Present study deals with studying aroma compounds behaviour from dilute and semi-dilute aqueous polysaccharide solutions consisting of different guar gum samples. Results allow stating that the whole polymer characteristics as determined by means of structural analysis, protein content determination, rheological and surface tension measurements play a major role on the polysaccharide/aroma compound interaction mechanisms. In particular, results evidence a strong Mannose to Galactose (M/G) ratio effect, thus allowing stating the occurrence of hydrophobic intra and intermolecular mechanism. In addition to that, proteins are demonstrated to only slightly affect the volatile retention. More generally, such an original study allows new highlights concerning macromolecular organisation and interactions in solution.     

Potent Anticancer Efficacy of First-In-Class CuII and AuIII Metaled Phosphorus Dendrons with Distinct Cell Death Pathways

First-in-class Cu^II and Au^III metaled phosphorus dendrons were synthesized and showed significant antiproliferative activity against several aggressive breast cancer cell lines. The data suggest that the cytotoxicity increases with reducing length of the alkyl chains, whereas the replacement of Cu^II with Au^III considerably increases the antiproliferative activity of metaled phosphorus dendrons. Very interestingly, we found that the cell death pathway is related to the nature of the metal complexed by the plain dendrons. Cu^II metaled dendrons showed a potent caspase-independent cell death pathway, whereas Au^III metaled dendrons displayed a caspase-dependent apoptotic pathway. The complexation of plain dendrons with Au^III increased the cellular lethality versus dendrons with Cu^II and promoted the translocation of Bax into the mitochondria and the release of Cytochrome C (Cyto C).     

Interactions of 3, 3.5, 4, and 4.5 generations of poly(amido amine) dendrimer with cationic surfactants

The conductivity (κ), turbidity (τ), NMR, and Krafft temperature (T _K) studies have been carried out for hexadecylpyridinium bromide (HPyBr), hexadecylpyridinium chloride (HPyCl), and hexadecyltrimethylammonium bromide (HTAB) in the presence of 3G, 3.5G, 4G, and 4.5G generations of poly(amido amine) dendrimers (PAMAM) in aqueous phase. The cmc of all present surfactants were evaluated from κ and τ measurements, both in the presence as well as in the absence of PAMAM. The cmc values decrease in the presence of PAMAM in comparison to that in pure water, especially in the presence of amine terminated PAMAM. Krafft temperature values of pure surfactants also decrease in the presence of various generations of PAMAM. A comparison of all present results from different techniques indicates that HPyBr interacts more strongly with all generations of PAMAM rather than HPyCl and HTAB.