Jesús Jiménez-barbero | CIC bioGUNE (original) (raw)

Papers by Jesús Jiménez-barbero

Research paper thumbnail of Recent Developments in Synthetic Carbohydrate-Based Diagnostics, Vaccines, and Therapeutics

Chemistry (Weinheim an der Bergstrasse, Germany), Jan 10, 2015

Glycans are everywhere in biological systems, being involved in many cellular events with importa... more Glycans are everywhere in biological systems, being involved in many cellular events with important implications for medical purposes. Building upon a detailed understanding of the functional roles of carbohydrates in molecular recognition processes and disease states, glycans are increasingly being considered as key players in pharmacological research. On the basis of the important progress recently made in glycochemistry, glycobiology, and glycomedicine, we provide a complete overview of successful applications and future perspectives of carbohydrates in the biopharmaceutical and medical fields. This review highlights the development of carbohydrate-based diagnostics, exemplified by glycan imaging techniques and microarray platforms, synthetic oligosaccharide vaccines against infectious diseases (e.g., HIV) and cancer, and finally carbohydrate-derived therapeutics, including glycomimetic drugs and glycoproteins.

Research paper thumbnail of Conformational Plasticity in Glycomimetics: Fluorocarbamethyl-L-idopyranosides Mimic the Intrinsic Dynamic Behaviour of Natural Idose Rings

Chemistry (Weinheim an der Bergstrasse, Germany), Jan 10, 2015

Sugar function, structure and dynamics are intricately correlated. Ring flexibility is intrinsica... more Sugar function, structure and dynamics are intricately correlated. Ring flexibility is intrinsically related to biological activity; actually plasticity in L-iduronic rings modulates their interactions with biological receptors. However, the access to the experimental values of the energy barriers and free-energy difference for conformer interconversion in water solution has been elusive. Here, a new generation of fluorine-containing glycomimetics is presented. We have applied a combination of organic synthesis, NMR spectroscopy and computational methods to investigate the conformational behaviour of idose- and glucose-like rings. We have used low-temperature NMR spectroscopic experiments to slow down the conformational exchange of the idose-like rings. Under these conditions, the exchange rate becomes slow in the (19) F NMR spectroscopic chemical shift timescale and allows shedding light on the thermodynamic and kinetic features of the equilibrium. Despite the minimal structural di...

Research paper thumbnail of The use of the MM3∗ and ESFF force fields in conformational analysis of carbohydrate molecules in solution: The methyl α-lactoside case

Journal of Molecular Structure: THEOCHEM, 1997

Research paper thumbnail of Glycans in Medicinal Chemistry: An Underexploited Resource

ChemMedChem, 2015

The biological relevance of glycans as mediators of key physiological processes, including diseas... more The biological relevance of glycans as mediators of key physiological processes, including disease-related mechanisms, makes them attractive targets for a wide range of medical applications. Despite their important biological roles, especially as molecular recognition elements, carbohydrates have not been fully exploited as therapeutics mainly due to the scarcity of structure-activity correlations and their non-drug-like properties. A more detailed understanding of the complex carbohydrate structures and their associated functions should contribute to the development of new glycan-based pharmaceuticals. Recent significant progress in oligosaccharide synthesis and chemical glycobiology has renewed the interest of the medicinal chemistry community in carbohydrates. This promises to increase our possibilities to harness them in drug discovery efforts for the development of new and more effective, synthetic glycan-based therapeutics and vaccines.

Research paper thumbnail of The Crystal Structure and Small-Angle X-Ray Analysis of CsdL/TcdA Reveal a New tRNA Binding Motif in the MoeB/E1 Superfamily

PLOS ONE, 2015

Cyclic N6-threonylcarbamoyladenosine (&am... more Cyclic N6-threonylcarbamoyladenosine ('cyclic t6A', ct6A) is a non-thiolated hypermodification found in transfer RNAs (tRNAs) in bacteria, protists, fungi and plants. In bacteria and yeast cells ct6A has been shown to enhance translation fidelity and efficiency of ANN codons by improving the faithful discrimination of aminoacylated tRNAs by the ribosome. To further the understanding of ct6A biology we have determined the high-resolution crystal structures of CsdL/TcdA in complex with AMP and ATP, an E1-like activating enzyme from Escherichia coli, which catalyzes the ATP-dependent dehydration of t6A to form ct6A. CsdL/TcdA is a dimer whose structural integrity and dimer interface depend critically on strongly bound K+ and Na+ cations. By using biochemical assays and small-angle X-ray scattering we show that CsdL/TcdA can associate with tRNA with a 1:1 stoichiometry and with the proper position and orientation for the cyclization of t6A. Furthermore, we show by nuclear magnetic resonance that CsdL/TcdA engages in transient interactions with CsdA and CsdE, which, in the latter case, involve catalytically important residues. These short-lived interactions may underpin the precise channeling of sulfur atoms from cysteine to CsdL/TcdA as previously characterized. In summary, the combination of structural, biophysical and biochemical methods applied to CsdL/TcdA has afforded a more thorough understanding of how the structure of this E1-like enzyme has been fine tuned to accomplish ct6A synthesis on tRNAs while providing support for the notion that CsdA and CsdE are able to functionally interact with CsdL/TcdA.

Research paper thumbnail of Discovery and Characterization of an Endogenous CXCR4 Antagonist

Research paper thumbnail of New inhibitors of angiogenesis with antitumor activity in vivo

Journal of Medicinal Chemistry, 2015

Research paper thumbnail of Solution conformation and dynamics of a tetrasaccharide related to the Lewis(x) antigen deduced by NMR relaxation measurements

Journal of biomolecular NMR, 1997

1H-NMR cross-relaxation rates and nonselective longitudinal relaxation times have been obtained a... more 1H-NMR cross-relaxation rates and nonselective longitudinal relaxation times have been obtained at two magnetic fields (7.0 and 11.8 T) and at a variety of temperatures for the branched tetrasaccharide methyl 3-O-alpha-N-acetyl-galactosaminyl-beta-galactopyranosyl-(1-->4)[3-O-alph a -fucosyl]-glucopyranoside (1), an inhibitor of astrocyte growth. In addition, 13C-NMR relaxation data have also been recorded at both fields. The 1H-NMR relaxation data have been interpreted using different motional models to obtain proton-proton correlation times. The results indicate that the GalNAc and Fuc rings display more extensive local motion than the two inner Glc and Gal moieties, since those present significantly shorter local correlation times. The 13C-NMR relaxation parameters have been interpreted in terms of the Lipari-Szabo model-free approach. Thus, order parameters and internal motion correlation times have been deduced. As obtained for the 1H-NMR relaxation data, the two outer resid...

Research paper thumbnail of Protein molecular weight standards can compensate systematic errors in diffusion-ordered spectroscopy

Analytical Biochemistry, 2004

Research paper thumbnail of Synthesis, Conformational Studies and Mannosidase Stability of a Mimic of 1,2-Mannobioside

European Journal of Organic Chemistry, 2004

Dimethyl (1S, 2S, 4S, 5S)-4-allyloxy-5-(α-mannosyloxy) cyclohexane-1, 2-dicarboxylate (3) was des... more Dimethyl (1S, 2S, 4S, 5S)-4-allyloxy-5-(α-mannosyloxy) cyclohexane-1, 2-dicarboxylate (3) was designed as a structural mimic of α (1, 2) mannobioside (1). Its synthesis and structural analysis by NMR spectroscopy and molecular modelling are described. The results show ...

Research paper thumbnail of A comparison of the geometry and of the energy results obtained by application of different molecular mechanics force fields to methyl α-lactoside and the C-analogue of lactose

Carbohydrate Research, 1997

The applicability of a number of standard molecular mechanics force fields, namely AMBER/Homans, ... more The applicability of a number of standard molecular mechanics force fields, namely AMBER/Homans, CVFF, CFF91, ESFF, and MM3∗, and of the AMI semiempirical Hamiltonian, to the molecular modelling of methyl α-lactoside is described. A protocol based on the calculation of relaxed energy maps for a significant number of initial structures has been employed. Different dielectric constants, as well as a

Research paper thumbnail of Polyhydroxyazepanes Mimicking Monosaccharides: Synthesis of an a-D-Galacto-like Iminoheptitol

Research paper thumbnail of Solution structure of the trisaccharide and hexasaccharide fragments of the O-antigen of the lipopolysaccharide of Rhizobium tropici CIAT899

Carbohydrate Research, 1995

Research paper thumbnail of Experimental and theoretical evidences of conformational flexibility of C-glycosides. NMR analysis and molecular mechanics calculations of C-lactose and its O-analogue

Tetrahedron Letters, 1995

NMR data (NOEs and coupling constants) and MM3∗ molecular mechanics calculations have allowed to ... more NMR data (NOEs and coupling constants) and MM3∗ molecular mechanics calculations have allowed to demonstrate that the conformational behaviour of C-lactose is different of its O-analogue. The glycosidic linkages, particularly the C-aglyconic bond, present a high degree of flexibility and, therefore, the conformational entropy of C-lactose is higher than that of its O-counterpart.

Research paper thumbnail of NMR Determination of the Bioactive Conformation of Peloruside A Bound To Microtubules

Journal of The American Chemical Society, 2006

Research paper thumbnail of Solution conformation and dynamics of an extracellular polysaccharide isolated from Bradyrhyzobium as deduced from 1H-NMR off resonance ROESY and 13C-NMR relaxation measurements

Carbohydrate Research, 1997

The conformational and dynamical features of an extracellular branched deacetylated polysaccharid... more The conformational and dynamical features of an extracellular branched deacetylated polysaccharide isolated from Bradyrhizobium (Chamaecytisus proliferus) have been investigated by homo and heteronuclear NMR methods. 1H-NMR cross relaxation rates have been obtained for this polysaccharide through regular NOESY and ROESY spectra as well as by modern off resonance ROESY techniques. Local proton-proton correlation times as well as interproton distances have

Research paper thumbnail of Conformational Flexibility of a Synthetic Glycosylaminoglycan Bound to a Fibroblast Growth Factor. FGF1 Recognizes Both the 1 C 4 and 2 S O Conformations of a Bioactive Heparin-like Hexasaccharide

Journal of The American Chemical Society, 2005

The first direct NMR determination of the conformation of a conformationally flexible heparin-lik... more The first direct NMR determination of the conformation of a conformationally flexible heparin-like hexasaccharide bound to a key receptor, FGF-1, is described. The determination has been based on the use of a 13C-labeled protein and a regular 12C sugar. FGF-1 recognizes several conformations of the iduronic moieties of the hexasaccharide. Therefore, this case is different than that described for the controversial recognition of heparin-like saccharides by AT-III, which seems to recognize just one conformation of the iduronic acid residues.

Research paper thumbnail of Taxanes with high potency inducing tubulin assembly overcome tumoural cell resistances

Bioorganic & Medicinal Chemistry, 2014

We have found that four taxanes with chemical modifications at positions C10 and C13 were active ... more We have found that four taxanes with chemical modifications at positions C10 and C13 were active against all types of taxane resistant cell lines, resistant by P-gp overexpression, by mutations in the β-tubulin binding site or by overexpression of the highly dynamic βIII-tubulin isotype. We have characterized the interaction of taxanes with high activity on chemotherapy resistant tumoural cells with microtubules, and also studied their cellular effects. The biochemical property enhanced in comparison with other taxanes is their potency at inducing tubulin assembly, despite the fact that their interactions with the microtubule binding sites (pore and luminal) are similar as studied by NMR and SAXS. A differential interaction with the S7-S9 loop (M-loop) is responsible for their enhanced assembly induction properties. The chemical changes in the structure also induce changes in the thermodynamic properties of the interaction, indicating a higher hydrophilicity and also explaining their properties on P-gp and βIII overexpressing cells and on mutant cells. The effect of the compounds on the microtubular network is different from those observed with the classical (docetaxel and paclitaxel) taxanes, inducing different bundling in cells with microtubules being very short, indicating a very fast nucleation effect and reflecting their high assembly induction power.

Research paper thumbnail of NMR experiments for the measurement of proton-proton and carbon-carbon residual dipolar couplings in uniformly labelled oligosaccharides

Research paper thumbnail of Polyhydroxyazepanes mimicking monosaccharides: Synthesis of an α-D-galacto-like iminoheptitol

Research paper thumbnail of Recent Developments in Synthetic Carbohydrate-Based Diagnostics, Vaccines, and Therapeutics

Chemistry (Weinheim an der Bergstrasse, Germany), Jan 10, 2015

Glycans are everywhere in biological systems, being involved in many cellular events with importa... more Glycans are everywhere in biological systems, being involved in many cellular events with important implications for medical purposes. Building upon a detailed understanding of the functional roles of carbohydrates in molecular recognition processes and disease states, glycans are increasingly being considered as key players in pharmacological research. On the basis of the important progress recently made in glycochemistry, glycobiology, and glycomedicine, we provide a complete overview of successful applications and future perspectives of carbohydrates in the biopharmaceutical and medical fields. This review highlights the development of carbohydrate-based diagnostics, exemplified by glycan imaging techniques and microarray platforms, synthetic oligosaccharide vaccines against infectious diseases (e.g., HIV) and cancer, and finally carbohydrate-derived therapeutics, including glycomimetic drugs and glycoproteins.

Research paper thumbnail of Conformational Plasticity in Glycomimetics: Fluorocarbamethyl-L-idopyranosides Mimic the Intrinsic Dynamic Behaviour of Natural Idose Rings

Chemistry (Weinheim an der Bergstrasse, Germany), Jan 10, 2015

Sugar function, structure and dynamics are intricately correlated. Ring flexibility is intrinsica... more Sugar function, structure and dynamics are intricately correlated. Ring flexibility is intrinsically related to biological activity; actually plasticity in L-iduronic rings modulates their interactions with biological receptors. However, the access to the experimental values of the energy barriers and free-energy difference for conformer interconversion in water solution has been elusive. Here, a new generation of fluorine-containing glycomimetics is presented. We have applied a combination of organic synthesis, NMR spectroscopy and computational methods to investigate the conformational behaviour of idose- and glucose-like rings. We have used low-temperature NMR spectroscopic experiments to slow down the conformational exchange of the idose-like rings. Under these conditions, the exchange rate becomes slow in the (19) F NMR spectroscopic chemical shift timescale and allows shedding light on the thermodynamic and kinetic features of the equilibrium. Despite the minimal structural di...

Research paper thumbnail of The use of the MM3∗ and ESFF force fields in conformational analysis of carbohydrate molecules in solution: The methyl α-lactoside case

Journal of Molecular Structure: THEOCHEM, 1997

Research paper thumbnail of Glycans in Medicinal Chemistry: An Underexploited Resource

ChemMedChem, 2015

The biological relevance of glycans as mediators of key physiological processes, including diseas... more The biological relevance of glycans as mediators of key physiological processes, including disease-related mechanisms, makes them attractive targets for a wide range of medical applications. Despite their important biological roles, especially as molecular recognition elements, carbohydrates have not been fully exploited as therapeutics mainly due to the scarcity of structure-activity correlations and their non-drug-like properties. A more detailed understanding of the complex carbohydrate structures and their associated functions should contribute to the development of new glycan-based pharmaceuticals. Recent significant progress in oligosaccharide synthesis and chemical glycobiology has renewed the interest of the medicinal chemistry community in carbohydrates. This promises to increase our possibilities to harness them in drug discovery efforts for the development of new and more effective, synthetic glycan-based therapeutics and vaccines.

Research paper thumbnail of The Crystal Structure and Small-Angle X-Ray Analysis of CsdL/TcdA Reveal a New tRNA Binding Motif in the MoeB/E1 Superfamily

PLOS ONE, 2015

Cyclic N6-threonylcarbamoyladenosine (&am... more Cyclic N6-threonylcarbamoyladenosine ('cyclic t6A', ct6A) is a non-thiolated hypermodification found in transfer RNAs (tRNAs) in bacteria, protists, fungi and plants. In bacteria and yeast cells ct6A has been shown to enhance translation fidelity and efficiency of ANN codons by improving the faithful discrimination of aminoacylated tRNAs by the ribosome. To further the understanding of ct6A biology we have determined the high-resolution crystal structures of CsdL/TcdA in complex with AMP and ATP, an E1-like activating enzyme from Escherichia coli, which catalyzes the ATP-dependent dehydration of t6A to form ct6A. CsdL/TcdA is a dimer whose structural integrity and dimer interface depend critically on strongly bound K+ and Na+ cations. By using biochemical assays and small-angle X-ray scattering we show that CsdL/TcdA can associate with tRNA with a 1:1 stoichiometry and with the proper position and orientation for the cyclization of t6A. Furthermore, we show by nuclear magnetic resonance that CsdL/TcdA engages in transient interactions with CsdA and CsdE, which, in the latter case, involve catalytically important residues. These short-lived interactions may underpin the precise channeling of sulfur atoms from cysteine to CsdL/TcdA as previously characterized. In summary, the combination of structural, biophysical and biochemical methods applied to CsdL/TcdA has afforded a more thorough understanding of how the structure of this E1-like enzyme has been fine tuned to accomplish ct6A synthesis on tRNAs while providing support for the notion that CsdA and CsdE are able to functionally interact with CsdL/TcdA.

Research paper thumbnail of Discovery and Characterization of an Endogenous CXCR4 Antagonist

Research paper thumbnail of New inhibitors of angiogenesis with antitumor activity in vivo

Journal of Medicinal Chemistry, 2015

Research paper thumbnail of Solution conformation and dynamics of a tetrasaccharide related to the Lewis(x) antigen deduced by NMR relaxation measurements

Journal of biomolecular NMR, 1997

1H-NMR cross-relaxation rates and nonselective longitudinal relaxation times have been obtained a... more 1H-NMR cross-relaxation rates and nonselective longitudinal relaxation times have been obtained at two magnetic fields (7.0 and 11.8 T) and at a variety of temperatures for the branched tetrasaccharide methyl 3-O-alpha-N-acetyl-galactosaminyl-beta-galactopyranosyl-(1-->4)[3-O-alph a -fucosyl]-glucopyranoside (1), an inhibitor of astrocyte growth. In addition, 13C-NMR relaxation data have also been recorded at both fields. The 1H-NMR relaxation data have been interpreted using different motional models to obtain proton-proton correlation times. The results indicate that the GalNAc and Fuc rings display more extensive local motion than the two inner Glc and Gal moieties, since those present significantly shorter local correlation times. The 13C-NMR relaxation parameters have been interpreted in terms of the Lipari-Szabo model-free approach. Thus, order parameters and internal motion correlation times have been deduced. As obtained for the 1H-NMR relaxation data, the two outer resid...

Research paper thumbnail of Protein molecular weight standards can compensate systematic errors in diffusion-ordered spectroscopy

Analytical Biochemistry, 2004

Research paper thumbnail of Synthesis, Conformational Studies and Mannosidase Stability of a Mimic of 1,2-Mannobioside

European Journal of Organic Chemistry, 2004

Dimethyl (1S, 2S, 4S, 5S)-4-allyloxy-5-(α-mannosyloxy) cyclohexane-1, 2-dicarboxylate (3) was des... more Dimethyl (1S, 2S, 4S, 5S)-4-allyloxy-5-(α-mannosyloxy) cyclohexane-1, 2-dicarboxylate (3) was designed as a structural mimic of α (1, 2) mannobioside (1). Its synthesis and structural analysis by NMR spectroscopy and molecular modelling are described. The results show ...

Research paper thumbnail of A comparison of the geometry and of the energy results obtained by application of different molecular mechanics force fields to methyl α-lactoside and the C-analogue of lactose

Carbohydrate Research, 1997

The applicability of a number of standard molecular mechanics force fields, namely AMBER/Homans, ... more The applicability of a number of standard molecular mechanics force fields, namely AMBER/Homans, CVFF, CFF91, ESFF, and MM3∗, and of the AMI semiempirical Hamiltonian, to the molecular modelling of methyl α-lactoside is described. A protocol based on the calculation of relaxed energy maps for a significant number of initial structures has been employed. Different dielectric constants, as well as a

Research paper thumbnail of Polyhydroxyazepanes Mimicking Monosaccharides: Synthesis of an a-D-Galacto-like Iminoheptitol

Research paper thumbnail of Solution structure of the trisaccharide and hexasaccharide fragments of the O-antigen of the lipopolysaccharide of Rhizobium tropici CIAT899

Carbohydrate Research, 1995

Research paper thumbnail of Experimental and theoretical evidences of conformational flexibility of C-glycosides. NMR analysis and molecular mechanics calculations of C-lactose and its O-analogue

Tetrahedron Letters, 1995

NMR data (NOEs and coupling constants) and MM3∗ molecular mechanics calculations have allowed to ... more NMR data (NOEs and coupling constants) and MM3∗ molecular mechanics calculations have allowed to demonstrate that the conformational behaviour of C-lactose is different of its O-analogue. The glycosidic linkages, particularly the C-aglyconic bond, present a high degree of flexibility and, therefore, the conformational entropy of C-lactose is higher than that of its O-counterpart.

Research paper thumbnail of NMR Determination of the Bioactive Conformation of Peloruside A Bound To Microtubules

Journal of The American Chemical Society, 2006

Research paper thumbnail of Solution conformation and dynamics of an extracellular polysaccharide isolated from Bradyrhyzobium as deduced from 1H-NMR off resonance ROESY and 13C-NMR relaxation measurements

Carbohydrate Research, 1997

The conformational and dynamical features of an extracellular branched deacetylated polysaccharid... more The conformational and dynamical features of an extracellular branched deacetylated polysaccharide isolated from Bradyrhizobium (Chamaecytisus proliferus) have been investigated by homo and heteronuclear NMR methods. 1H-NMR cross relaxation rates have been obtained for this polysaccharide through regular NOESY and ROESY spectra as well as by modern off resonance ROESY techniques. Local proton-proton correlation times as well as interproton distances have

Research paper thumbnail of Conformational Flexibility of a Synthetic Glycosylaminoglycan Bound to a Fibroblast Growth Factor. FGF1 Recognizes Both the 1 C 4 and 2 S O Conformations of a Bioactive Heparin-like Hexasaccharide

Journal of The American Chemical Society, 2005

The first direct NMR determination of the conformation of a conformationally flexible heparin-lik... more The first direct NMR determination of the conformation of a conformationally flexible heparin-like hexasaccharide bound to a key receptor, FGF-1, is described. The determination has been based on the use of a 13C-labeled protein and a regular 12C sugar. FGF-1 recognizes several conformations of the iduronic moieties of the hexasaccharide. Therefore, this case is different than that described for the controversial recognition of heparin-like saccharides by AT-III, which seems to recognize just one conformation of the iduronic acid residues.

Research paper thumbnail of Taxanes with high potency inducing tubulin assembly overcome tumoural cell resistances

Bioorganic & Medicinal Chemistry, 2014

We have found that four taxanes with chemical modifications at positions C10 and C13 were active ... more We have found that four taxanes with chemical modifications at positions C10 and C13 were active against all types of taxane resistant cell lines, resistant by P-gp overexpression, by mutations in the β-tubulin binding site or by overexpression of the highly dynamic βIII-tubulin isotype. We have characterized the interaction of taxanes with high activity on chemotherapy resistant tumoural cells with microtubules, and also studied their cellular effects. The biochemical property enhanced in comparison with other taxanes is their potency at inducing tubulin assembly, despite the fact that their interactions with the microtubule binding sites (pore and luminal) are similar as studied by NMR and SAXS. A differential interaction with the S7-S9 loop (M-loop) is responsible for their enhanced assembly induction properties. The chemical changes in the structure also induce changes in the thermodynamic properties of the interaction, indicating a higher hydrophilicity and also explaining their properties on P-gp and βIII overexpressing cells and on mutant cells. The effect of the compounds on the microtubular network is different from those observed with the classical (docetaxel and paclitaxel) taxanes, inducing different bundling in cells with microtubules being very short, indicating a very fast nucleation effect and reflecting their high assembly induction power.

Research paper thumbnail of NMR experiments for the measurement of proton-proton and carbon-carbon residual dipolar couplings in uniformly labelled oligosaccharides

Research paper thumbnail of Polyhydroxyazepanes mimicking monosaccharides: Synthesis of an α-D-galacto-like iminoheptitol