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14 pages, 2894 KiB

Open AccessFeature PaperArticle

New Morphiceptin Peptidomimetic Incorporating (1S,2R,3S,4S,5R)-2-Amino-3,4,5-trihydroxycyclopen-tane-1-carboxylic acid: Synthesis and Structural Study

by Raquel Soengas, Marcos Lorca, Begoña Pampín, Víctor M. Sánchez-Pedregal, Ramón J. Estévez and Juan C. Estévez

Molecules 2020, 25(11), 2574; https://doi.org/10.3390/molecules25112574 - 1 Jun 2020

Cited by 3 | Viewed by 2676

Abstract

We present the synthesis and structural study of a new peptidomimetic of morphiceptin, which can formally be considered as the result of the replacement of the central proline residue of this natural analgesic drug with a subunit of (1S,2R,3 [...] Read more.

We present the synthesis and structural study of a new peptidomimetic of morphiceptin, which can formally be considered as the result of the replacement of the central proline residue of this natural analgesic drug with a subunit of (1S,2R,3S,4S,5R)-2-amino-3,4,5-trihydroxycyclopentane-1-carboxylic acid, previously obtained from L-idose. An optimized synthesis of this trihydroxylated cispentacin derivative is also reported. Molecular docking calculations on the target receptor support a favorable role of the hydroxy substituents of the non-natural β-amino acid incorporated into the peptidomimetic. Full article

(This article belongs to the Special Issue Carbohydrates in Synthesis)

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19 pages, 5495 KiB

Open AccessArticle

Synthesis and Glycosidase Inhibition of Broussonetine M and Its Analogues

by Qing-Kun Wu, Kyoko Kinami, Atsushi Kato, Yi-Xian Li, Yue-Mei Jia, George W. J. Fleet and Chu-Yi Yu

Molecules 2019, 24(20), 3712; https://doi.org/10.3390/molecules24203712 - 15 Oct 2019

Cited by 12 | Viewed by 3069

Abstract

Cross-metathesis (CM) and Keck asymmetric allylation, which allows access to defined stereochemistry of a remote side chain hydroxyl group, are the key steps in a versatile synthesis of broussonetine M (3) from the d-arabinose-derived cyclic nitrone 14. By a [...] Read more.

Cross-metathesis (CM) and Keck asymmetric allylation, which allows access to defined stereochemistry of a remote side chain hydroxyl group, are the key steps in a versatile synthesis of broussonetine M (3) from the d-arabinose-derived cyclic nitrone 14. By a similar strategy, ent-broussonetine M (ent-3) and six other stereoisomers have been synthesized, respectively, starting from l-arabino-nitrone (ent-14), l-lyxo-nitrone (ent-3-epi-14), and l-xylo-nitrone (2-epi-14) in five steps, in 26%–31% overall yield. The natural product broussonetine M (3) and 10’-epi-3 were potent inhibitors of β-glucosidase (IC₅₀ = 6.3 μM and 0.8 μM, respectively) and β-galactosidase (IC₅₀ = 2.3 μM and 0.2 μM, respectively); while their enantiomers, ent-3 and ent-10’-epi-3, were selective and potent inhibitors of rice α-glucosidase (IC₅₀ = 1.2 μM and 1.3 μM, respectively) and rat intestinal maltase (IC₅₀ = 0.29 μM and 18 μM, respectively). Both the configuration of the polyhydroxylated pyrrolidine ring and C-10’ hydroxyl on the alkyl side chain affect the specificity and potency of glycosidase inhibition. Full article

(This article belongs to the Special Issue Carbohydrates in Synthesis)

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14 pages, 1580 KiB

Open AccessArticle

Synthesis of a Di-Mycoloyl Tri-Arabinofuranosyl Glycerol Fragment of the Mycobacterial Cell Wall, Based on Synthetic Mycolic Acids

by Omar T. Ali, Mohsin O. Mohammed, Juma’a R. Al Dulayymi and Mark S. Baird

Molecules 2019, 24(19), 3596; https://doi.org/10.3390/molecules24193596 - 6 Oct 2019

Cited by 4 | Viewed by 2376

Abstract

Fragments of mycobacterial cell walls such as arabinoglycerol mycolate and dimycoloyl diarabinoglycerol, comprising complex mixtures of mycolic acids, have immunostimulatory and antigenic properties. A related di-mycoloyl tri-arabinofuranosyl glycerol fragment has been isolated from cell wall hydrolysates. An effective stereoselective synthesis of tri-arabinofuranosyl glycerol, [...] Read more.

Fragments of mycobacterial cell walls such as arabinoglycerol mycolate and dimycoloyl diarabinoglycerol, comprising complex mixtures of mycolic acids, have immunostimulatory and antigenic properties. A related di-mycoloyl tri-arabinofuranosyl glycerol fragment has been isolated from cell wall hydrolysates. An effective stereoselective synthesis of tri-arabinofuranosyl glycerol, followed by coupling with stereochemically defined mycolic acids of different structural classes, to provide unique di-mycoloyl tri-arabinofuranosyl glycerols is now described. Full article

(This article belongs to the Special Issue Carbohydrates in Synthesis)

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19 pages, 3402 KiB

Open AccessArticle

Selectively Charged and Zwitterionic Analogues of the Smallest Immunogenic Structure of Streptococcus Pneumoniae Type 14

by Tiziana Gragnani, Doretta Cuffaro, Silvia Fallarini, Grazia Lombardi, Felicia D’Andrea and Lorenzo Guazzelli

Molecules 2019, 24(18), 3414; https://doi.org/10.3390/molecules24183414 - 19 Sep 2019

Cited by 1 | Viewed by 3405

Abstract

Zwitterionic polysaccharides (ZPs) have been shown in recent years to display peculiar immunological properties, thus attracting the interest of the carbohydrate research community. To fully elucidate the mechanisms underlying these properties and exploit the potential of this kind of structures, in depth studies [...] Read more.

Zwitterionic polysaccharides (ZPs) have been shown in recent years to display peculiar immunological properties, thus attracting the interest of the carbohydrate research community. To fully elucidate the mechanisms underlying these properties and exploit the potential of this kind of structures, in depth studies are still required. In this context, the preparation of two cationic, an anionic, as well as two zwitterionic tetrasaccharide analogues of the smallest immunogenic structure of Streptococcus pneumoniae type 14 (SP14) capsular polysaccharide are presented. By exploiting a block strategy, the negative charge has been installed on the non-reducing end of the lactose unit of the tetrasaccharide and the positive charge either on the non-reducing end of the lactosamine moiety or on an external linker. These structures have then been tested by competitive ELISA, showing that the structural variations we made do not modify the affinity of the neutral compound to binding to a specific antibody. However, lower efficacies than the natural SP14 compound were observed. The results obtained, although promising, point to the need to further elongate the polysaccharide structure, which is likely too short to cover the entire epitopes. Full article

(This article belongs to the Special Issue Carbohydrates in Synthesis)

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10 pages, 2102 KiB

Open AccessArticle

Synthesis of Fucosyl-Oligosaccharides Using α-l-Fucosidase from Lactobacillus rhamnosus GG

by Yolanda Escamilla-Lozano, Francisco Guzmán-Rodríguez, Sergio Alatorre-Santamaría, Mariano García-Garibay, Lorena Gómez-Ruiz, Gabriela Rodríguez-Serrano and Alma Cruz-Guerrero

Molecules 2019, 24(13), 2402; https://doi.org/10.3390/molecules24132402 - 29 Jun 2019

Cited by 11 | Viewed by 4308

Abstract

Fucosyl-oligosaccharides are natural prebiotics that promote the growth of probiotics in human gut and stimulate the innate immune system. In this work, the release of α-lfucosidase by Lactobacillus rhamnosus GG, and the use of this enzyme for the synthesis of fucosyl-oligosaccharides [...] Read more.

Fucosyl-oligosaccharides are natural prebiotics that promote the growth of probiotics in human gut and stimulate the innate immune system. In this work, the release of α-lfucosidase by Lactobacillus rhamnosus GG, and the use of this enzyme for the synthesis of fucosyl-oligosaccharides were investigated. Since α-lfucosidase is a membrane-bound enzyme, its release from the cells was induced by addition of 4-nitrophenyl-α-l-fucopyranoside (pNP-Fuc). Enzyme activity associated with the cell was recovered at 78% of its total activity. Fucosyl-oligosaccharides where synthesized using α-l-fucosidase extract and pNP-Fuc as donor substrate, and D-lactose or D-lactulose as acceptor substrates, reaching a yield up to 25%. Fucosyllactose was obtained as a reaction product with D-lactose, and its composition was confirmed by mass spectrometry (MALDI-TOF MS). It is possible that the fucosyl-oligosaccharide synthesized in this study has biological functions similar to human milk oligosaccharides. Full article

(This article belongs to the Special Issue Carbohydrates in Synthesis)

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15 pages, 4316 KiB

Open AccessArticle

2-Ketogluconate Kinase from Cupriavidus necator H16: Purification, Characterization, and Exploration of Its Substrate Specificity

by Israel Sánchez-Moreno, Natalia Trachtmann, Sibel Ilhan, Virgil Hélaine, Marielle Lemaire, Christine Guérard-Hélaine and Georg A. Sprenger

Molecules 2019, 24(13), 2393; https://doi.org/10.3390/molecules24132393 - 28 Jun 2019

Cited by 3 | Viewed by 3373

Abstract

We have cloned, overexpressed, purified, and characterized a 2-ketogluconate kinase (2-dehydrogluconokinase, EC 2.7.1.13) from Cupriavidus necator (Ralstonia eutropha) H16. Exploration of its substrate specificity revealed that three ketoacids (2-keto-3-deoxy-d-gluconate, 2-keto-d-gulonate, and 2-keto-3-deoxy-d-gulonate) with structures close to the [...] Read more.

We have cloned, overexpressed, purified, and characterized a 2-ketogluconate kinase (2-dehydrogluconokinase, EC 2.7.1.13) from Cupriavidus necator (Ralstonia eutropha) H16. Exploration of its substrate specificity revealed that three ketoacids (2-keto-3-deoxy-d-gluconate, 2-keto-d-gulonate, and 2-keto-3-deoxy-d-gulonate) with structures close to the natural substrate (2-keto-d-gluconate) were successfully phosphorylated at an efficiency lower than or comparable to 2-ketogluconate, as depicted by the measured kinetic constant values. Eleven aldo and keto monosaccharides of different chain lengths and stereochemistries were also assayed but not found to be substrates. 2-ketogluconate-6-phosphate was synthesized at a preparative scale and was fully characterized for the first time. Full article

(This article belongs to the Special Issue Carbohydrates in Synthesis)

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17 pages, 4248 KiB

Open AccessArticle

Unraveling Sugar Binding Modes to DC-SIGN by Employing Fluorinated Carbohydrates

by J. Daniel Martínez, Pablo Valverde, Sandra Delgado, Cecilia Romanò, Bruno Linclau, Niels C. Reichardt, Stefan Oscarson, Ana Ardá, Jesús Jiménez-Barbero and F. Javier Cañada

Molecules 2019, 24(12), 2337; https://doi.org/10.3390/molecules24122337 - 25 Jun 2019

Cited by 38 | Viewed by 5951

Abstract

A fluorine nuclear magnetic resonance (¹⁹F-NMR)-based method is employed to assess the binding preferences and interaction details of a library of synthetic fluorinated monosaccharides towards dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN), a lectin of biomedical interest, which is involved [...] Read more.

A fluorine nuclear magnetic resonance (¹⁹F-NMR)-based method is employed to assess the binding preferences and interaction details of a library of synthetic fluorinated monosaccharides towards dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN), a lectin of biomedical interest, which is involved in different viral infections, including HIV and Ebola, and is able to recognize a variety of self- and non-self-glycans. The strategy employed allows not only screening of a mixture of compounds, but also obtaining valuable information on the specific sugar–protein interactions. The analysis of the data demonstrates that monosaccharides Fuc, Man, Glc, and Gal are able to bind DC-SIGN, although with decreasing affinity. Moreover, a new binding mode between Man moieties and DC-SIGN, which might have biological implications, is also detected for the first time. The combination of the ¹⁹F with standard proton saturation transfer difference (¹H-STD-NMR) data, assisted by molecular dynamics (MD) simulations, permits us to successfully define this new binding epitope, where Man coordinates a Ca²⁺ ion of the lectin carbohydrate recognition domain (CRD) through the axial OH-2 and equatorial OH-3 groups, thus mimicking the Fuc/DC-SIGN binding architecture. Full article

(This article belongs to the Special Issue Carbohydrates in Synthesis)

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17 pages, 2486 KiB

Open AccessArticle

Synthesis of a Fluorous-Tagged Hexasaccharide and Interaction with Growth Factors Using Sugar-Coated Microplates

by Susana Maza, José L. de Paz and Pedro M. Nieto

Molecules 2019, 24(8), 1591; https://doi.org/10.3390/molecules24081591 - 22 Apr 2019

Cited by 5 | Viewed by 2985

Abstract

Here, we report the synthesis of a sulfated, fully protected hexasaccharide as a glycosaminoglycan mimetic and the study of its interactions with different growth factors: midkine, basic fibroblast growth factor (FGF-2) and nerve growth factor (NGF). Following a fluorous-assisted approach, monosaccharide building blocks [...] Read more.

Here, we report the synthesis of a sulfated, fully protected hexasaccharide as a glycosaminoglycan mimetic and the study of its interactions with different growth factors: midkine, basic fibroblast growth factor (FGF-2) and nerve growth factor (NGF). Following a fluorous-assisted approach, monosaccharide building blocks were successfully assembled and the target oligosaccharide was prepared in excellent yield. The use of more acid stable 4,6-O-silylidene protected glucosamine units was crucial for the efficiency of this strategy because harsh reaction conditions were needed in the glycosylations to avoid the formation of orthoester side products. Fluorescence polarization experiments demonstrated the strong interactions between the synthesized hexamer, and midkine and FGF-2. In addition, we have developed an alternative assay to analyse these molecular recognition events. The prepared oligosaccharide was non-covalently attached to a fluorous-functionalized microplate and the direct binding of the protein to the sugar-immobilized surface was measured, affording the corresponding K_D,surf value. Full article

(This article belongs to the Special Issue Carbohydrates in Synthesis)

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Review

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22 pages, 954 KiB

Open AccessReview

Synthesis of Human Milk Oligosaccharides: Protein Engineering Strategies for Improved Enzymatic Transglycosylation

by Birgitte Zeuner, David Teze, Jan Muschiol and Anne S. Meyer

Molecules 2019, 24(11), 2033; https://doi.org/10.3390/molecules24112033 - 28 May 2019

Cited by 85 | Viewed by 10478

Abstract

Human milk oligosaccharides (HMOs) signify a unique group of oligosaccharides in breast milk, which is of major importance for infant health and development. The functional benefits of HMOs create an enormous impetus for biosynthetic production of HMOs for use as additives in infant [...] Read more.

Human milk oligosaccharides (HMOs) signify a unique group of oligosaccharides in breast milk, which is of major importance for infant health and development. The functional benefits of HMOs create an enormous impetus for biosynthetic production of HMOs for use as additives in infant formula and other products. HMO molecules can be synthesized chemically, via fermentation, and by enzymatic synthesis. This treatise discusses these different techniques, with particular focus on harnessing enzymes for controlled enzymatic synthesis of HMO molecules. In order to foster precise and high-yield enzymatic synthesis, several novel protein engineering approaches have been reported, mainly concerning changing glycoside hydrolases to catalyze relevant transglycosylations. The protein engineering strategies for these enzymes range from rationally modifying specific catalytic residues, over targeted subsite −1 mutations, to unique and novel transplantations of designed peptide sequences near the active site, so-called loop engineering. These strategies have proven useful to foster enhanced transglycosylation to promote different types of HMO synthesis reactions. The rationale of subsite −1 modification, acceptor binding site matching, and loop engineering, including changes that may alter the spatial arrangement of water in the enzyme active site region, may prove useful for novel enzyme-catalyzed carbohydrate design in general. Full article

(This article belongs to the Special Issue Carbohydrates in Synthesis)

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