-
Marine Drugs Jul 2019To date, a number of mannose-specific lectins have been isolated and characterized from seaweeds, especially from red algae. In fact, man-specific seaweed lectins... (Review)
Review
To date, a number of mannose-specific lectins have been isolated and characterized from seaweeds, especially from red algae. In fact, man-specific seaweed lectins consist of different structural scaffolds harboring a single or a few carbohydrate-binding sites which specifically recognize mannose-containing glycans. Depending on the structural scaffold, man-specific seaweed lectins belong to five distinct structurally-related lectin families, namely (1) the griffithsin lectin family (β-prism I scaffold); (2) the agglutinin homolog (OAAH) lectin family (β-barrel scaffold); (3) the legume lectin-like lectin family (β-sandwich scaffold); (4) the agglutinin (GNA)-like lectin family (β-prism II scaffold); and, (5) the MFP2-like lectin family (MFP2-like scaffold). Another algal lectin from , has been inferred to the methanol dehydrogenase related lectin family, because it displays a rather different GlcNAc-specificity. In spite of these structural discrepancies, all members from the five lectin families share a common ability to specifically recognize man-containing glycans and, especially, high-mannose type glycans. Because of their mannose-binding specificity, these lectins have been used as valuable tools for deciphering and characterizing the complex mannose-containing glycans from the glycocalyx covering both normal and transformed cells, and as diagnostic tools and therapeutic drugs that specifically recognize the altered high-mannose -glycans occurring at the surface of various cancer cells. In addition to these anti-cancer properties, man-specific seaweed lectins have been widely used as potent human immunodeficiency virus (HIV-1)-inactivating proteins, due to their capacity to specifically interact with the envelope glycoprotein gp120 and prevent the virion infectivity of HIV-1 towards the host CD4+ T-lymphocyte cells in vitro.
Topics: Amino Acid Sequence; Animals; Antineoplastic Agents; Humans; Mannose; Mannose-Binding Lectins; Rhodophyta
PubMed: 31357490
DOI: 10.3390/md17080440 -
Carbohydrate Research Sep 20232-Deoxy-d-glucose (2-DG), a compound known to interfere with d-glucose and d-mannose metabolism, has been tested as a potential anticancer and antiviral agent....
2-Deoxy-d-glucose (2-DG), a compound known to interfere with d-glucose and d-mannose metabolism, has been tested as a potential anticancer and antiviral agent. Preclinical and clinical studies focused on 2-DG have highlighted several limitations related to 2-DG drug-like properties, such as poor pharmacokinetic properties. To overcome this problem, we proposed design and synthesis of novel 2-DG prodrugs that subsequently could be tested using a variety of biochemical and molecular methods. We narrowed here our focus to esters of 2-DG as potential prodrugs based on the hypothesis that ubiquitous esterases will regenerate 2-DG, leading to increased circulation time of drug and adequate organ and tumor penetration. Testing this hypothesis in vitro and, especially, in vivo requires significant amounts of respective pure mono- and previously unknown di-acetylated water-soluble derivatives of 2-DG. Development of their efficient and practical method of synthesis was imperative. We describe novel facile and scalable syntheses of seven selectively acetylated water-soluble derivatives of 2-DG and present a detailed H and C NMR analysis of all final products. X-ray diffraction analysis has been performed for compound WP1122 that was selected for detailed preclinical and subsequent clinical evaluation as potential anticancer or antiviral agent.
Topics: Glucose; Antimetabolites; Mannose; Prodrugs; Deoxyglucose; Antiviral Agents
PubMed: 37356236
DOI: 10.1016/j.carres.2023.108861 -
ACS Infectious Diseases Nov 2020Biofilms are one of the most challenging obstacles in bacterial infections. By providing protection against immune responses and antibiotic therapies, biofilms enable...
Biofilms are one of the most challenging obstacles in bacterial infections. By providing protection against immune responses and antibiotic therapies, biofilms enable chronic colonization and the development of antibiotic resistance. As previous clinical observations and studies have shown, traditional antibiotic therapy alone cannot effectively treat and eliminate biofilm forming infections due to the protection conferred by the biofilm. A new strategy specifically targeting biofilms must be developed. Here, we specifically target and bind to the PAO1 biofilm and elucidate the molecular mechanism behind the interaction between a glycan targeted polymer and biofilm using a continuous flow biofilm model. The incubation of biofilms with fluorescent glycan targeted polymers demonstrated strong and persistent interactions with the mannose-containing polymer even after 24 h of continuous flow. To evaluate the role of major biofilm proteins LecB and CdrA, loss of function experiments with knockout variants established the dual involvement of both proteins in mannose targeted polymer retention. These results identify a persistent and specific targeting strategy to the biofilm, emphasizing its potential value as a delivery strategy and encouraging further exploration of biofilm targeted delivery.
Topics: Bacterial Proteins; Biofilms; Mannose; Polymers; Pseudomonas aeruginosa
PubMed: 33074651
DOI: 10.1021/acsinfecdis.0c00407 -
Current Opinion in Cell Biology Aug 2016Protein O-mannosylation and N-glycosylation are essential post-translational modifications, which initiate in the endoplasmic reticulum (ER). In yeast, the two... (Review)
Review
Protein O-mannosylation and N-glycosylation are essential post-translational modifications, which initiate in the endoplasmic reticulum (ER). In yeast, the two glycosylation machineries act at the Sec61 translocon complex where they can even compete for certain substrate proteins. N-linked glycans play a crucial role in the ER quality control of glycoproteins. In recent years, it became clear that in addition to its important functions for cell surface proteins, O-mannosylation impacts the ER protein homeostasis. These glycans can exclude unfavorable folding intermediates from futile folding attempts, increase the solubility of irreversibly misfolded proteins, and even mark them for degradation. O-Mannose glycoproteomics now captures the molecular complexity of this modification opening exciting opportunities to explore further roles of O-mannosylation in the early secretory pathway.
Topics: Animals; Endoplasmic Reticulum; Glycosylation; Humans; Mannose; Proteins; Saccharomyces cerevisiae; Secretory Pathway
PubMed: 27161930
DOI: 10.1016/j.ceb.2016.04.010 -
The Journal of Physical Chemistry. A Mar 2019Gas phase, isolated monosaccharides arabinose- and mannose-related anionic species generated through the matrix-assisted laser desorption ionization (MALDI) method are...
Gas phase, isolated monosaccharides arabinose- and mannose-related anionic species generated through the matrix-assisted laser desorption ionization (MALDI) method are investigated via negative ion photoelectron spectroscopy (PES) and density functional theory (DFT) calculations. The vertical detachment energies (VDEs) of the observed anionic species are experimentally determined: the corresponding structures are assigned based on good agreement between experimental and theoretical VDEs. Arabinose parent anion is found to exist as open chain structures in the gas phase, while mannose parent anionic species are not observed. Both monosaccharides undergo dissociation through loss of H and loss of HO. (saccharide-H) anions evidence coexisting positional and conformational isomers. (saccharide-HO) species have only two positional isomers, each with conformational differences. The present results for arabinose and mannose are further compared to those previously reported for ribose and fructose. This comparison is based on the anions observed and identified through the same PES/DFT techniques for the four saccharides (arabinose, mannose, ribose, and fructose). The issue of natural selection of ribose as the sugar backbone constituent of RNA is thereby explored from the point of view of anionic electronic structure and stability of the four species. Saccharide phosphates are also discussed in the present work with regard to addressing the unique natural selection of ribose for the backbone support of RNA and DNA.
Topics: Anions; Arabinose; Density Functional Theory; Fructose; Mannose; Models, Chemical; Molecular Conformation; Photoelectron Spectroscopy; Ribose; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
PubMed: 30807168
DOI: 10.1021/acs.jpca.8b11838 -
Biochimica Et Biophysica Acta. General... Nov 2020Mutations in the PMM2 gene cause phosphomannomutase 2 deficiency (PMM2; MIM# 212065), which manifests as a congenital disorder of glycosylation (PMM2-CDG). Mutant PMM2... (Review)
Review
BACKGROUND
Mutations in the PMM2 gene cause phosphomannomutase 2 deficiency (PMM2; MIM# 212065), which manifests as a congenital disorder of glycosylation (PMM2-CDG). Mutant PMM2 leads to the reduced conversion of Man-6-P to Man-1-P, which results in low concentrations of guanosine 5'-diphospho-D-mannose, a nucleotide-activated sugar essential for the construction of protein oligosaccharide chains. To date the only therapeutic options are preventive and symptomatic.
SCOPE OF REVIEW
This review covers the latest advances in the search for a treatment for PMM2-CDG.
MAJOR CONCLUSIONS
Treatments based on increasing Man-1-P levels have been proposed, along with the administration of different mannose derivates, employing enzyme inhibitors or repurposed drugs to increase the synthesis of GDP-Man. A single repurposed drug that might alleviate a severe neurological symptom associated with the disorder is now in clinical use. Proof of concept also exists regarding the use of pharmacological chaperones and/or proteostatic regulators to increase the concentration of hypomorphic PMM2 mutant proteins.
GENERAL SIGNIFICANCE
The ongoing challenges facing the discovery of drugs to treat this orphan disease are discussed.
Topics: Animals; Antisense Elements (Genetics); Congenital Disorders of Glycosylation; Drug Discovery; Enzyme Inhibitors; Glycosylation; Humans; Mannose; Phosphotransferases (Phosphomutases)
PubMed: 32712172
DOI: 10.1016/j.bbagen.2020.129686 -
Advanced Materials (Deerfield Beach,... May 2023Multiresponsive adjuvant nanoparticles (RMmAGL) are fabricated to perform tumor-specific photothermal therapy while regulating the behavior of tumor-associated immune...
Multiresponsive adjuvant nanoparticles (RMmAGL) are fabricated to perform tumor-specific photothermal therapy while regulating the behavior of tumor-associated immune cells for primary tumor eradication and metastasis inhibition. Core-satellite-like RMmAGL have a core of mannose-functionalized mesoporous silica nanoparticles loaded with the TLR7 agonist imiquimod (R837@MSN-mannose) connected via hydrazone bonds to satellites of glutamine (Glu)- and lysine (Lys)-comodified gold nanoparticles (AuNPs-Glu/Lys). During therapy, the acidic environment in tumor tissue cleaves the hydrazone bonds to release AuNPs-Glu/Lys, which further accumulate in tumor cells. After internalization, photothermal agents (aggregated AuNPs-Glu/Lys) are generated in situ through the intratumoral enzyme-catalyzed reaction between Glu and Lys, resulting in tumor-specific photothermal therapy. The detachment of AuNPs-Glu/Lys also triggers the release of R837, which matured dendritic cells (DCs) via a vaccine-like mechanism along with the tumor-associated antigens generated by photothermal therapy. These matured DCs further activates surrounding T cells for immunotherapy. Moreover, the resulting free MSN-mannose serves as an artificial glycocalyx to continuously induce the polarization of tumor-associated macrophages from an immunosuppressive phenotype to an inflammatory phenotype, thus further enhancing immunotherapy. Both in vivo and in vitro experiments demonstrate significant inhibition of malignant tumors after therapy.
Topics: Humans; Adjuvants, Immunologic; Cell Line, Tumor; Gold; Immunotherapy; Mannose; Metal Nanoparticles; Neoplasms; Photothermal Therapy
PubMed: 36782382
DOI: 10.1002/adma.202300086 -
Advanced Science (Weinheim,... Jan 2024Targeting the niche components surrounding glioblastoma stem cells (GSCs) helps to develop more effective glioblastoma treatments. However, the mechanisms underlying the...
Targeting the niche components surrounding glioblastoma stem cells (GSCs) helps to develop more effective glioblastoma treatments. However, the mechanisms underlying the crosstalk between GSCs and microenvironment remain largely unknown. Clarifying the extracellular molecules binding to GSCs marker CD133 helps to elucidate the mechanism of the communication between GSCs and the microenvironment. Here, it is found that the extracellular domain of high mannose type CD133 physically interacts with Collagen 1 (COL1) in GSCs. COL1, mainly secreted by cancer-associated fibroblasts, is a niche component for GSCs. COL1 enhances the interaction between CD133 and p85 and activates Akt phosphorylation. Activation of Akt pathway increases transcription factor ATF4 protein level, subsequently enhances SLC1A5-dependent glutamine uptake and glutathione synthesis. The inhibition of CD133-COL1 interaction or down-regulation of SLC1A5 reduces COL1-accelerated GSCs self-renewal and tumorigenesis. Analysis of glioma samples reveals that the level of COL1 is correlated with histopathological grade of glioma and the expression of SLC1A5. Collectively, COL1, a niche component for GSCs, enhances the tumorigenesis of GSCs partially through CD133-Akt-SLC1A5 signaling axis, providing a new mechanism underlying the cross-talk between GSCs and extracellular matrix (ECM) microenvironment.
Topics: Humans; Glioblastoma; Glutamine; Mannose; Proto-Oncogene Proteins c-akt; Neoplastic Stem Cells; Carcinogenesis; Cell Transformation, Neoplastic; Glioma; Collagen; Tumor Microenvironment; Minor Histocompatibility Antigens; Amino Acid Transport System ASC
PubMed: 37997289
DOI: 10.1002/advs.202306715 -
Chemistry (Weinheim An Der Bergstrasse,... Oct 2022Dendrimers are appealing scaffolds for creating carbohydrate mimics with unique multivalent cooperativity. We report here novel bola-amphiphilic glycodendrimers bearing...
Dendrimers are appealing scaffolds for creating carbohydrate mimics with unique multivalent cooperativity. We report here novel bola-amphiphilic glycodendrimers bearing mannose and glucose terminals, and a hydrophobic thioacetal core responsive to reactive oxygen species. The peculiar bola-amphiphilic feature enabled stronger binding to lectin compared to conventional amphiphiles. In addition, these dendrimers are able to target mannose receptors and glucose transporters expressed at the surface of cells, thus allowing effective and specific cellular uptake. This highlights their great promise for targeted delivery.
Topics: Mannose; Dendrimers; Reactive Oxygen Species; Carbohydrates; Lectins; Glucose
PubMed: 35820051
DOI: 10.1002/chem.202201400 -
Bioengineered Dec 2021Raman spectroscopy was applied to an aqueous solution containing D-mannose and D-glucose at a fixed dry matter content. The Raman measurement apparatus was adapted...
Raman spectroscopy was applied to an aqueous solution containing D-mannose and D-glucose at a fixed dry matter content. The Raman measurement apparatus was adapted online at the industrial scale to monitor a bioprocess including an epimerization reaction. Online Raman spectroscopy and deconvolution techniques were successfully applied to monitor in real time the D-mannose and D-glucose concentrations using the Raman shifts at 960 cm and 974 cm respectively. The two anomeric forms, α and β of D-mannose in the pyranose conformation were quantified. In silico analysis of vibrational frequencies and Raman intensities of hydrated structure of D-mannose and D-glucose in the pyranose form for α and β anomers were carried out using a two-step procedure. First molecular dynamics was used to generate the theoretical carbohydrates' structures keeping the experimental dry matter content, then quantum mechanics was used to compute the Raman frequencies and intensities. Computed vibrational frequencies are in satisfactory agreement with the experimental spectra considering a hydration shell approach. Raman intensities are qualitatively in accordance with the experimental data. The interpretation of Raman frequencies and intensities led to acceptable results regarding the current possible structures of D-mannose and D-glucose in aqueous solution. Online Raman spectroscopy coupled with in silico approaches such as quantum mechanics and molecular dynamics methodology is proved to be a valuable tool to quantify the carbohydrates and stereoisomers content in complex aqueous mixtures. This methodology offers a new way to monitor any bioprocesses that encounter aqueous mixtures of D-glucose and D-mannose.
Topics: Glucose; Mannose; Molecular Dynamics Simulation; Spectrum Analysis, Raman; Vibration; Water
PubMed: 34308749
DOI: 10.1080/21655979.2021.1955550