Person:
Hernáiz Gómez-Degano, María Josefa

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First Name
María Josefa
Last Name
Hernáiz Gómez-Degano
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Farmacia
Department
Química en Ciencias Farmacéuticas
Area
Química Orgánica
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UCM identifierScopus Author IDDialnet ID

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Now showing 1 - 10 of 10
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Expanding the synthesis of a library of potent glucuronic acid glycodendrons for Dengue virus inhibition

2023-12, Ramírez López, Pedro, Carlos Martínez, Alejandro Merchán, Perona Requena, Almudena, Hernáiz Gómez-Degano, María Josefa, Hernáiz, MJ

Multivalent glycodendrons are valuable tools to mimic many structural and functional features of cell-surface glycoconjugates and its focal position scaffolds represent important components to increase specificity and affinity. Previous work in our group described the preparation of a tetravalent glucuronic acid dendron that binds with good affinity to Dengue virus envelope protein (KD = 22 mu M). Herein, the chemical synthesis and binding analysis of a new library of potent glucuronic acid dendrons bearing different functional group at the focal position and different level of multivalency are described. Their chemical synthesis was performed sequentially in three stages and with good yields. Namely a) the chemical synthesis of the oligo and polyalkynyl scaffolds, b) assembling with fully protected glucuronic acid-based azide units by using a microwave assisted copper-catalysed azide-alkyne cycloaddition reaction and c) sequential deprotection of hydroxyl and carboxylic acid groups.Surface Plasmon Resonance studies have demonstrated that the valency and the focal position functional group exert influence on the interaction with Dengue virus envelope protein. Molecular modelling studies were carried out in order to understand the binding observed. This work reports an efficient glycodendrons chemical synthesis that provides appropriate focal position functional group and multivalence, that offer an easy and versatile strategy to find new active compounds against Dengue virus.

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Highly Efficient and Sustainable Synthesis of Neoglycoproteins Using Galactosidases

2020-03-02, Hoyos Vidal, María Pilar, Bavaro, Teodora, Perona Requena, Almudena, Rumbero, Angel, Tengattini, S, Terreni, Marco, Hernáiz Gómez-Degano, María Josefa, Hernáiz Gómez-Degano, María Josefa

Oligosaccharides are a key component on glycoconjugates with biomedical applications. However, the investigation of more efficient and environmental protocols for their preparation carrying defined oligosaccharides remains a big challenge due to lack of access to structurally well-defined and functionalized oligosaccharides. In this work a highly sustainable and efficient chemoenzymatic synthesis of neo-glycoproteins in green solvents was studied. In particular, we described the preparation of new activated disaccharides useful for direct protein binding under mild reaction conditions, reducing the protection/activation steps commonly needed in the traditional synthetic routes. Thus, N-acetylglucosamine (GlcNAc) was functionalized with a thiocyanomethyl group at C-1 and employed for the first time as acceptor in the enzymatic synthesis of the disaccharide of interest using β-Gal-3 from Bacillus circulans and β-galactosidase from Escherichia coli. The use of biosolvents promotes a very important increase of the enzymatic activity in the synthesis of functionalized Gal-β-(1 → 6)-GlcNAc (95%) preventing hydrolytic activity with full regioselectivity. Furthermore, reaction scaling up and biosolvent recycling are feasible without losing catalytic action. The enzyme–substrate recognition and the effect of biosolvent over the galactosidases activity has been investigated and explained by computational modeling studies. The presence of C-1 thiocyanomethyl moiety strongly hindered the normal course of transglycosylation for β-Gal-3 afforded β(1 → 6) glyosidic linkage instead of β(1 → 3). Then, this functionalized disaccharide has been activated with imino methoxyethyl (IME) linker and conjugated to ribonuclease A (RNase A). The glycosylation of RNase A, with IME-disaccharide provided the corresponding neo-glycoprotein with 85% of yield. This work opens to a new, simple, and green way to synthesize innovative glycoconjugate vaccines.

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Development of sustainable synthesis of glucuronic acid glycodendrimers using ball milling and microwave-assisted CuAAC reaction

2022-03-08, García Oliva, Cecilia María, Merchán, Alejandro , Perona Requena, Almudena, Hoyos Vidal, María Pilar, Rumbero, Ángel , Hernáiz Gómez-Degano, María Josefa

Two green strategies for copper-catalyzed azide-alkyne cycloaddition reaction based on two activation pathways, solvent free mechanochemistry and microwave irradiation using a recycable biosolvent, are reported for the synthesis of glucuronic acid glycodendrimers with good conversions (99%), the MW pathway being the ideal tool (90% yield in 90 min).

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Enzymatic Synthesis and Molecular Modelling Studies of Rhamnose Esters Using Lipase from Pseudomonas stutzeri

2022-02-17, Hernáiz Gómez-Degano, María Josefa, Perona Requena, Almudena, Rumbero, Ángel , Hoyos Vidal, María Pilar, García Oliva, Cecilia María, Hernáiz Gómez-Degano, María Josefa

Rhamnolipids are becoming an important class of glycolipid biosurfactants. Herein, we describe for the first time the enzymatic synthesis of rhamnose fatty acid esters by the transesterification of rhamnose with fatty acid vinyl esters, using lipase from Pseudomonas stutzeri as a biocatalyst. The use of this lipase allows excellent catalytic activity in the synthesis of 4-O-acylrhamnose (99% conversion and full regioselectivity) after 3 h of reaction using tetrahydrofuran (THF) as the reaction media and an excess of vinyl laurate as the acyl donor. The role of reaction conditions, such as temperature, the substrates molar ratio, organic reaction medium and acyl donor chain-length, was studied. Optimum conditions were found using 35 °C, a molar ratio of 1:3 (rhamnose:acyldonor), solvents with a low logP value, and fatty acids with chain lengths from C4 to C18 as acyl donors. In hydrophilic solvents such as THF and acetone, conversions of up to 99–92% were achieved after 3 h of reaction. In a more sustainable solvent such as 2-methyl-THF (2-MeTHF), high conversions were also obtained (86%). Short and medium chain acyl donors (C4–C10) allowed maximum conversions after 3 h, and long chain acyl donors (C12–C18) required longer reactions (5 h) to get 99% conversions. Furthermore, scaled up reactions are feasible without losing catalytic action and regioselectivity. In order to explain enzyme regioselectivity and its ability to accommodate ester chains of different lengths, homology modelling, docking studies and molecular dynamic simulations were performed to explain the behaviour observed.

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Current challenges and future perspectives in sustainable mechanochemical transformations of carbohydrates

2020, Hoyos Vidal, María Pilar, Perona Requena, Almudena, Ángeles Farrán, Hernáiz Gómez-Degano, María Josefa, Hernáiz, MJ, Royal Society of Chemistry

The use of mechanochemistry in carbohydrate chemistry is currently a growing field in which many new developments are being made because of its potential application in green methodologies. Ball milling (BM) is a promising eco-friendly technique with excellent characteristics that allows mostly solvent-free, faster and energy-efficient reactions. In this context, we provide in this perspective review a critical summary and discussion of the main known synthetic methods for carbohydrates based on mechanochemistry. The combination of the promising properties of mechanochemistry with carbohydrate reactions can be advantageous for setting strategies aligned with the green chemistry principles.

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Expanding the synthesis of a library of potent glucuronic acid glycodendrons for Dengue virus inhibition

2023-12, Ramírez López, Pedro, Martínez Espinosa, Carlos Antonio, Merchán, Alejandro , Perona Requena, Almudena, Hernáiz Gómez-Degano, María Josefa

Multivalent glycodendrons are valuable tools to mimic many structural and functional features of cell-surface glycoconjugates and its focal position scaffolds represent important components to increase specificity and affinity. Previous work in our group described the preparation of a tetravalent glucuronic acid dendron that binds with good affinity to Dengue virus envelope protein (KD = 22 μM). Herein, the chemical synthesis and binding analysis of a new library of potent glucuronic acid dendrons bearing different functional group at the focal position and different level of multivalency are described. Their chemical synthesis was performed sequentially in three stages and with good yields. Namely a) the chemical synthesis of the oligo and polyalkynyl scaffolds, b) assembling with fully protected glucuronic acid-based azide units by using a microwave assisted copper-catalysed azide-alkyne cycloaddition reaction and c) sequential deprotection of hydroxyl and carboxylic acid groups. Surface Plasmon Resonance studies have demonstrated that the valency and the focal position functional group exert influence on the interaction with Dengue virus envelope protein. Molecular modelling studies were carried out in order to understand the binding observed. This work reports an efficient glycodendrons chemical synthesis that provides appropriate focal position functional group and multivalence, that offer an easy and versatile strategy to find new active compounds against Dengue virus.

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Enzymatic Synthesis and Molecular Modelling Studies of Rhamnose Esters Using Lipase from Pseudomonas stutzeri

2022-02-17, Perona Requena, Almudena, García Oliva, Cecilia María, Rumbero, Ángel, Hoyos Vidal, María Pilar, Hernáiz Gómez-Degano, María Josefa, Hernáiz Gómez-Degano, María Josefa

Rhamnolipids are becoming an important class of glycolipid biosurfactants. Herein, we describe for the first time the enzymatic synthesis of rhamnose fatty acid esters by the transesterification of rhamnose with fatty acid vinyl esters, using lipase from Pseudomonas stutzeri as a biocatalyst. The use of this lipase allows excellent catalytic activity in the synthesis of 4-O-acylrhamnose (99% conversion and full regioselectivity) after 3 h of reaction using tetrahydrofuran (THF) as the reaction media and an excess of vinyl laurate as the acyl donor. The role of reaction conditions, such as temperature, the substrates molar ratio, organic reaction medium and acyl donor chain-length, was studied. Optimum conditions were found using 35 °C, a molar ratio of 1:3 (rhamnose:acyldonor), solvents with a low logP value, and fatty acids with chain lengths from C4 to C18 as acyl donors. In hydrophilic solvents such as THF and acetone, conversions of up to 99–92% were achieved after 3 h of reaction. In a more sustainable solvent such as 2-methyl-THF (2-MeTHF), high conversions were also obtained (86%). Short and medium chain acyl donors (C4–C10) allowed maximum conversions after 3 h, and long chain acyl donors (C12–C18) required longer reactions (5 h) to get 99% conversions. Furthermore, scaled up reactions are feasible without losing catalytic action and regioselectivity. In order to explain enzyme regioselectivity and its ability to accommodate ester chains of different lengths, homology modelling, docking studies and molecular dynamic simulations were performed to explain the behaviour observed.

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Efficient Synthesis of Muramic and Glucuronic Acid Glycodendrimers as Dengue Virus Antagonists

2020-02-03, Cabanillas, Alfredo H, Rumbero, Ángel, García Oliva, Cecilia María, Perona Requena, Almudena, Hernáiz Gómez-Degano, María Josefa, Hoyos Vidal, María Pilar

Carbohydrates are involved in many important pathological processes, such as bacterial and viral infections, by means of carbohydrate-protein interactions. Glycoconjugates with multiple carbohydrates are involved in multivalent interactions, thus increasing their binding strengths to proteins. In this work, we report the efficient synthesis of novel muramic and glucuronic acid glycodendrimers as potential Dengue virus antagonists. Aromatic scaffolds functionalized with a terminal ethynyl groups were coupled to muramic and glucuronic acid azides by click chemistry through optimized synthetic strategies to afford the desired glycodendrimers with high yields. Surface Plasmon Resonance studies have demonstrated that the compounds reported bind efficiently to the Dengue virus envelope protein. Molecular modelling studies were carried out to simulate and explain the binding observed. These studies confirm that efficient chemical synthesis of glycodendrimers can be brought about easily offering a versatile strategy to find new active compounds against Dengue virus.

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Exploring Rigid and Flexible Scaffolds to Develop Potent Glucuronic Acid Glycodendrimers for Dengue Virus Inhibition

2023-11-15, Merchán, Alejandro , Ramírez López, Pedro, Martínez Espinosa, Carlos Antonio, Suárez Álvarez, José Ramón, Perona Requena, Almudena, Hernáiz Gómez-Degano, María Josefa

Multivalent glycodendrimers are valuable tools for studying carbohydrate-protein interactions, and their scaffolds represent important components to increase specificity and affinity. Previous work by our group described the preparation of a tetravalent glucuronic acid rigid dendron that binds with good affinity to the dengue virus envelope protein (KD = 22 μM). Herein, the chemical synthesis and binding analysis of three new sets of rigid, semirigid, and flexible glucuronic acid-based dendrimers bearing different levels of multivalency and their interactions with the dengue virus envelope protein are described. The different oligoalkynyl scaffolds were coupled to glucuronic acid azides by a copper-catalyzed azide-alkyne cycloaddition reaction through optimized synthetic strategies to afford the desired glycodendrimers with good yields. Surface plasmon resonance studies have demonstrated that glycodendrimers 12b and 12c, with flexible scaffolds, give the best binding interactions with the dengue virus envelope protein (12b: KD = 0.487 μM and 12c: KD = 0.624 μM). Their binding constant values were 45 and 35 times higher than the one obtained in previous studies with a rigid tetravalent glucuronic acid dendron (KD = 22 μM), respectively. Molecular modeling studies were carried out in order to understand the difference in behavior observed for 12b and 12c. This work reports an efficient glycodendrimer chemical synthesis process that provides an appropriate scaffold that offers an easy and versatile strategy to find new active compounds against the dengue virus.

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Synthesis of Glycodendrimers with Antiviral and Antibacterial Activity

2021-03-24, Hoyos Vidal, María Pilar, Juanes, Olga , Perona Requena, Almudena, Rumbero, Ángel , Hernáiz Gómez-Degano, María Josefa

Glycodendrimers are an important class of synthetic macromolecules that can be used to mimic many structural and functional features of cell‐surface glycoconjugates. Their carbohydrate moieties perform key important functions in bacterial and viral infections, often regulated by carbohydrate–protein interactions. Several studies have shown that the molecular structure, valency and spatial organisation of carbohydrate epitopes in glycoconjugates are key factors in the specificity and avidity of carbohydrate–protein interactions. Choosing the right glycodendrimers almost always helps to interfere with such interactions and blocks bacterial or viral adhesion and entry into host cells as an effective strategy to inhibit bacterial or viral infections. Herein, the state of the art in the design and synthesis of glycodendrimers employed for the development of anti‐adhesion therapy against bacterial and viral infections is described.