Some Human Anti-Glycan Antibodies Lack the Ability to Activate the Complement System.

Naturally occurring human antibodies against glycans recognize and quickly eliminate infectious bacteria, viruses and aberrantly glycosylated neoplastic malignant cells, and they often initiate processes that involve the complement system. Using a printed glycan array (PGA) containing 605 glycoligands (oligo- and polysaccharides, glycopeptides), we examined which of the glycan-binding antibodies are able to activate the complement system. Using this PGA, the specificities of antibodies of the IgM and IgG classes were determined in the blood serum of healthy donors (suggested as mostly natural), and, then, using the same array, it was determined which types of the bound immunoglobulins were also showing C3 deposition.

Antigen Presentation in an Artificial and Cell Membrane: Blood Group A Glycan Recognition.

Glycosphingolipids (GSL) are functionally important components of the cell membrane and recognition of their glycan "head" by the immune system is a key part of normal and pathological processes. Recognition of glycolipid antigens on a living cell, their structure, "context" (microenvironment and clustering), presentation including orientation and distance from the plasma membrane, as well as molecular dynamics are important. GSL antigens are targets for the development of anticancer vaccines and therapeutic antibodies, therefore, control of the presentation of their glycans by synthetic methods opens up new possibilities in medicine.

A novel syphilis Treponema pallidum lipoprotein peptide antigen diagnostic assay using red cell kodecytes in routine blood centre column agglutination testing platforms.

Background And Objectives: The detection of treponemal antibodies, which are used to make a diagnosis of syphilis, is important both for diagnostic purposes and as a mandatory blood donor test in most countries. We evaluated the feasibility of using Kode Technology to make syphilis peptide red cell kodecytes for use in column agglutination serologic platforms.

Materials And Methods: Candidate Kode Technology function-spacer-lipid (FSL) constructs were made for the Treponema pallidum lipoprotein (TmpA) of T.

Scyllatoxin-based peptide design for E. coli expression and HIV gp120 binding.

Targeting the hydrophobic Phe43 pocket of HIV's envelope glycoprotein gp120 is a critical strategy for antiviral interventions due to its role in interacting with the host cell's CD4. Previous inhibitors, including small molecules and CD4 mimetic peptides based on scyllatoxin, have demonstrated significant binding and neutralization capabilities but were often chemically synthesized or contained non-canonical amino acids. Microbial expression using natural amino acids offers advantages such as cost-effectiveness, scalability, and efficient production of fusion proteins.

Effect of ligand and shell densities on the surface structure of core-shell nanoparticles self-assembled from function-spacer-lipid constructs.

Biomolecular corona is the major obstacle to the clinical translation of nanomedicines. Since corona formation is governed by molecular interactions at the nano-bio interface, nanoparticle surface properties such as topography, charge and surface chemistry can be tuned to manipulate biomolecular corona formation. To this end, as the first step towards a deep understanding of the processes of corona formation, it is necessary to develop nanoparticles employing various biocompatible materials and characterize their surface structure and dynamics at the molecular level.

Virtual screening and identification of promising therapeutic compounds against drug-resistant β-ketoacyl-acyl carrier protein synthase I (KasA).

The emergence of new () strains resistant to the key drugs currently used in the clinic for tuberculosis treatment can substantially reduce the probability of therapy success, causing the relevance and importance of studies on the development of novel potent antibacterial agents targeting different vulnerable spots of . In this study, 28,860 compounds from the library of bioactive molecules were screened to identify novel potential inhibitors of β-ketoacyl-acyl carrier protein synthase I (KasA), one of the key enzymes involved in the biosynthesis of mycolic acids of the cell wall. In doing so, we used a structure-based virtual screening approach to drug repurposing that included high-throughput docking of the C171Q KasA enzyme with compounds from the library of bioactive molecules including the FDA-approved drugs and investigational drug candidates, assessment of the binding affinity for the docked ligand/C171Q KasA complexes, and molecular dynamics simulations followed by binding free energy calculations.

Repurposing Navitoclax to block SARS-CoV-2 fusion and entry by targeting heptapeptide repeat sequence 1 in S2 protein.

Along with the long pandemic of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has come the dilemma of emerging viral variants of concern (VOC), particularly Omicron and its subvariants, able to deftly escape immune surveillance and the otherwise protective effect of current vaccines and antibody drugs. We previously identified a peptide-based pan-CoV fusion inhibitor, termed as EK1, able to bind the HR1 region in viral spike (S) protein S2 subunit. This effectively blocked formation of the six-helix bundle (6-HB) fusion core and, thus, showed efficacy against all human coronaviruses (HCoVs).

AI-Driven De Novo Design and Molecular Modeling for Discovery of Small-Molecule Compounds as Potential Drug Candidates Targeting SARS-CoV-2 Main Protease.

Over the past three years, significant progress has been made in the development of novel promising drug candidates against COVID-19. However, SARS-CoV-2 mutations resulting in the emergence of new viral strains that can be resistant to the drugs used currently in the clinic necessitate the development of novel potent and broad therapeutic agents targeting different vulnerable spots of the viral proteins. In this study, two deep learning generative models were developed and used in combination with molecular modeling tools for de novo design of small molecule compounds that can inhibit the catalytic activity of SARS-CoV-2 main protease (Mpro), an enzyme critically important for mediating viral replication and transcription.

Antibodies against hyaluronan oligosaccharides in xenotransplantation.

Carbohydrate-specific antibodies are significant mediators of xenograft rejection. This study analyzed the carbohydrate specificity of antibodies in baboons before and after xenotransplantation of organs or injection of porcine red blood cells from hDAF transgenic pigs, using a glycan array with structurally defined glycans. Antibodies against hyaluronic acid disaccharide (HA2) showed the highest reactivity at baseline and rose after xenogeneic exposure.

Small-molecule HIV-1 entry inhibitors targeting the epitopes of broadly neutralizing antibodies.

Highly active antiretroviral therapy currently used for HIV/AIDS has significantly increased the life expectancy of HIV-infected individuals. It has also improved the quality of life, reduced mortality, and decreased the incidence of AIDS and HIV-related conditions. Currently, however, affected individuals are typically on a lifetime course of several therapeutic drugs, all with the potential for associated toxicity and emergence of resistance.

Lipopolysaccharide From Increases Glutamate-Induced Disturbances of Calcium Homeostasis, the Functional State of Mitochondria, and the Death of Cultured Cortical Neurons.

Lipopolysaccharide (LPS), a fragment of the bacterial cell wall, specifically interacting with protein complexes on the cell surface, can induce the production of pro-inflammatory and apoptotic signaling molecules, leading to the damage and death of brain cells. Similar effects have been noted in stroke and traumatic brain injury, when the leading factor of death is glutamate (Glu) excitotoxicity too. But being an amphiphilic molecule with a significant hydrophobic moiety and a large hydrophilic region, LPS can also non-specifically bind to the plasma membrane, altering its properties.

SARS-CoV-2 Peptide Bioconjugates Designed for Antibody Diagnostics.

In the near future, the increase in the number of required tests for COVID-19 antibodies is expected to be many hundreds of millions. Obviously, this will be done using a variety of analytical methods and using different antigens, including peptides. In this work, we compare three method variations for detecting specific immunoglobulins directed against peptides of approximately 15-aa of the SARS-CoV-2 spike protein.

Localization of synthetic glycolipids in the cell and the dynamics of their insertion/loss.

Modification of the cell surface with synthetic glycolipids opens up a wide range of possibilities for studying the function of glycolipids. Synthetic glycolipids called Function-Spacer-Lipids (FSL; where F is a glycan or label, S is a spacer, and L is dioleoylphosphatidyl ethanolamine) easily and controllably modify the membrane of a living cells. This current study investigates the dynamics and mechanism of the FSL insertion and release/loss.

Application of deep learning and molecular modeling to identify small drug-like compounds as potential HIV-1 entry inhibitors.

A generative adversarial autoencoder for the rational design of potential HIV-1 entry inhibitors able to block CD4-binding site of the viral envelope protein gp120 was developed. To do this, the following studies were carried out: (i) an autoencoder architecture was constructed; (ii) a virtual compound library of potential anti-HIV-1 agents for training the neural network was formed by the concept of click chemistry allowing one to generate a large number of drug candidates by their assembly from small modular units; (iii) molecular docking of all compounds from this library with gp120 was made and calculations of the values of binding free energy were performed; (iv) molecular fingerprints of chemical compounds from the training dataset were generated; (v) training of the developed autoencoder was implemented followed by the validation of this neural network using more than 21 million molecules from the ZINC15 database. As a result, three small drug-like compounds that exhibited the high-affinity binding to gp120 were identified.

Synthesis of bodipy-labeled bacterial polysaccharides and their interaction with human dendritic cells.

In this report, we describe the fluorescent labeling of bacterial polysaccharides (Escherichia coli O86:B7, Escherichia coli O19ab, Pseudomonas aeruginosa O10a10b, and Shigella flexneri 2b) at the "natural" amino group of their phosphoethanolamine moiety. Two protocols for labeling are compared: 1) on a scale of a few mg of the polysaccharide, with a dialysis procedure for purification from excessive reagents; and 2) on a scale of 0.1 mg of the polysaccharide, with a simple precipitation procedure instead of dialysis.

COVID-19 antibody screening with SARS-CoV-2 red cell kodecytes using routine serologic diagnostic platforms.

Background: The Coronavirus disease 2019 (COVID-19) pandemic is having a major global impact, and the resultant response in the development of new diagnostics is unprecedented. The detection of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a role in managing the pandemic. We evaluated the feasibility of using SARS-CoV-2 peptide Kode Technology-modified red cells (C19-kodecytes) to develop an assay compatible with existing routine serologic platforms.

40 years of glyco-polyacrylamide in glycobiology.

Polyacrylamide conjugates of glycans have long been widely used in many research areas of glycobiology, mainly for immobilizing glycans in solid-phase assays and as multivalent inhibitors. Pending biotin tag allows immobilizing Glyc-PAA quantitatively on any surface, and acts as a tracer for detection of carbohydrate-binding proteins. However, the scope of already realized capabilities of these probes is immeasurably richer than those listed above.

Structural motifs in protein cores and at protein-protein interfaces are different.

Structures of proteins and protein-protein complexes are determined by the same physical principles and thus share a number of similarities. At the same time, there could be differences because in order to function, proteins interact with other molecules, undergo conformations changes, and so forth, which might impose different restraints on the tertiary versus quaternary structures. This study focuses on structural properties of protein-protein interfaces in comparison with the protein core, based on the wealth of currently available structural data and new structure-based approaches.

Computational discovery of small drug-like compounds as potential inhibitors of SARS-CoV-2 main protease.

A computational approach to in drug discovery was carried out to identify small drug-like compounds able to show structural and functional mimicry of the high affinity ligand X77, potent non-covalent inhibitor of SARS-COV-2 main protease (M). In doing so, the X77-mimetic candidates were predicted based on the crystal X77-M structure by a public web-oriented virtual screening platform Pharmit. Models of these candidates bound to SARS-COV-2 M were generated by molecular docking, quantum chemical calculations and molecular dynamics simulations.

Structure of Supramers Formed by the Amphiphile Biotin-CMG-DOPE.

The synthetic function-spacer-lipid (FSL) amphiphile biotin-CMG-DOPE is widely used for delicate ligation of living cells with biotin residues under physiological conditions. Since this molecule has an "apolar-polar-hydrophobic" gemini structure, the supramolecular organization is expected to differ significantly from the classical micelle. Its organization is investigated with experimental methods and molecular dynamics simulations (MDS).

Structure of Supramers Formed by the Amphiphile Biotin-CMG-DOPE.

https://doi.org/10.1002/open.

In Silico Identification of Novel Aromatic Compounds as Potential HIV-1 Entry Inhibitors Mimicking Cellular Receptor CD4.

Despite recent progress in the development of novel potent HIV-1 entry/fusion inhibitors, there are currently no licensed antiviral drugs based on inhibiting the critical interactions of the HIV-1 envelope gp120 protein with cellular receptor CD4. In this connection, studies on the design of new small-molecule compounds able to block the gp120-CD4 binding are still of great value. In this work, in silico design of drug-like compounds containing the moieties that make the ligand active towards gp120 was performed within the concept of click chemistry.

Smart Complex Fluids Based on Two-Antennary Oligoglycines.

Antennary oligoglycines are synthetic products, obtained as a result of preliminary molecular design. Equal-length antennae are built of glycine residues joined through the C end to an oligoamine branching core with an amine group at the N terminus exposed outside. The results of systematic research on the properties of aqueous solutions containing two-antennary oligoglycine with four glycine portions are reported.