Artículos (Química Orgánica)

URI permanente para esta colecciónhttps://hdl.handle.net/11441/10924

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Monovalent glycoconjugates of sulforaphane prevent inflammation induced by lipopolysaccharide in human dendritic cells by inhibiting NF-ĸB signalling pathway
(John Wiley and Sons Inc, 2025-11) Leiva‐Castro, Camila; Múnera‐Rodríguez, Ana Maria; Martínez Bailén, Macarena; Carmona Asenjo, Ana Teresa; López Enríquez, Soledad; Palomares Jerez, María Francisca; Química Orgánica y Farmacéutica; Química Orgánica; Bioquímica Médica y Biología Molecular e Inmunología; Ministerio de Ciencia e Innovación (MICIN). España; Universidad de Sevilla
Background and Purpose: Sulforaphane (SFN) has notable health benefits but faces challenges due to its poor solubility and delivery. This study investigates SFN-glycoconjugates effects on lipopolysaccharide (LPS)-induced inflammation in dendritic cells (DCs). With the aiming to enhance their therapeutic potential against inflammatory diseases. Novel monovalent SFN-glycoconjugates with mannose (Man) and fucose (0Fuc) were developed and tested for their anti-inflammatory and immune-modulatory properties in DCs from healthy donors under chronic LPS exposure. Experimental Approach: By leveraging therapeutic strategies, SFN-glycoconjugates significantly improved the solubility and bioavailability of SFN, thereby overcoming the limitations of traditional delivery methods. Monocyte-derived DCs were treated with SFN-glycoconjugates and subsequently exposed to a chronic inflammatory environment induced by LPS. Key Results: Our results showed that SFN-glycoconjugates enhance effectiveness in suppressing inflammation by targeting the p65 NF-κB pathway, without affecting MAPK signalling. SFN-glycoconjugates induce a tolerogenic immune response, characterized by increased IL-10 production and enhanced regulatory T- and B-cell proliferation. These effects surpass those of p65 NF-κB inhibition alone, highlighting a distinct and potent regulatory mechanism independent of MAPK pathways. Conclusion and Implications: The integration of food therapeutic strategies not only enhances the stability and delivery of bioactive compounds but also broadens their potential applications in functional foods and therapeutic approaches. In particular, SFN-glycoconjugates represent a promising option as biologically active compounds for inflammatory diseases, offering enhanced anti-inflammatory and immunomodulatory effects through optimized delivery systems and the activation of specific molecular pathways.
Exploring substituent diversity on pyrrolidine-aryltriazole iminosugars: Structural basis of β-glucocerebrosidase inhibition
(Elsevier, 2019-05) Martínez Bailén, Macarena; Carmona Asenjo, Ana Teresa; Patterson-Orazem, Athéna C.; Lieberman, Raquel L.; Ide, Daisuke; Kubo, Moemi; Kato, Atsushi; Robina Ramírez, Inmaculada; Moreno Vargas, Antonio José; Química Orgánica; Ministerio de Economía y Competitividad (MINECO). España; Junta de Andalucía; Japanese Society for the Promotion of Science; National Institutes of Health. United States
The synthesis of a library of pyrrolidine-aryltriazole hybrids through CuAAC between two epimeric dihydroxylated azidomethylpyrrolidines and differently substituted phenylacetylenes is reported. The evaluation of the new compounds as inhibitors of lysosomal β-glucocerebrosidase showed the importance of the substitution pattern of the phenyl moiety in the inhibition. Crystallization and docking studies revealed key interactions of the pyrrolidine motif with aminoacid residues of the catalytic site while the aryltriazole moiety extended along a hydrophobic surface groove. Some of these compounds were able to increase the enzyme activity in Gaucher patient fibroblasts, acting as a new type of chemical chaperone for Gaucher disease.
Synthesis of multimeric pyrrolidine iminosugar inhibitors of human β-glucocerebrosidase and α-galactosidase A: First example of a multivalent enzyme activity enhancer for Fabry disease
(Elsevier, 2020-04-15) Martínez Bailén, Macarena; Carmona Asenjo, Ana Teresa; Cardona, Francesca; Matassini, Camilla; Goti, Andrea; Kubo, Moemi; Kato, Atsushi; Robina Ramírez, Inmaculada; Moreno Vargas, Antonio José; Química Orgánica; Ministerio de Economía y Competitividad (MINECO). España; Junta de Andalucía; Japanese Society for the Promotion of Science; Ente Cassa di Risparmio di Firenze
The synthesis of a chemical library of multimeric pyrrolidine-based iminosugars by incorporation of three pairs of epimeric pyrrolidine-azides into different alkyne scaffolds via CuAAC is presented. The new multimers were evaluated as inhibitors of two important therapeutic enzymes, human α-galactosidase A (α-Gal A) and lysosomal β-glucocerebrosidase (GCase). Structure-activity relationships were established focusing on the iminosugar inhitope, the valency of the dendron and the linker between the inhitope and the central scaffold. Remarkable is the result obtained in the inhibition of α-Gal A, where one of the nonavalent compounds showed potent inhibition (0.20 μM, competitive inhibition), being a 375-fold more potent inhibitor than the monovalent reference. The potential of the best α-Gal A inhibitors to act as pharmacological chaperones was analyzed by evaluating their ability to increase the activity of this enzyme in R301G fibroblasts from patients with Fabry disease, a genetic disorder related with a reduced activity of α-Gal A. The best enzyme activity enhancement was obtained for the same nonavalent compound, which increased 5.2-fold the activity of the misfolded enzyme at 2.5 μM, what constitutes the first example of a multivalent α-Gal A activity enhancer of potential interest in the treatment of Fabry disease.
Regioselectivity of the 1,3-Dipolar Cycloaddition of Organic Azides to 7-Heteronorbornadienes. Synthesis of beta-Substituted Furans/Pyrroles
(American Chemical Society, 2020-06-10) Gil de Montes Rojas, Enrique; Martínez Bailén, Macarena; Carmona Asenjo, Ana Teresa; Robina Ramírez, Inmaculada; Moreno Vargas, Antonio José; Química Orgánica; Ministerio de Economía y Competitividad (MINECO). España; Junta de Andalucía
An efficient procedure for the preparation of β-substituted furans/pyrroles is presented. The methodology is based on the use of 7-oxa/azanorbornadienes as dipolarophiles in 1,3-dipolar cycloaddition with benzyl azide. The triazoline cycloadduct thus formed spontaneously decomposes via a retro-Diels–Alder (rDA) reaction to afford a β-substituted furan/pyrrole derivative and a stable triazole. The scope of this tandem 1,3-dipolar cycloaddition/rDA reaction was studied with thirteen 7-heteronorbornadienes. This study allowed a deep knowledge of the regioselectivity of the reaction, which can be tuned through the substituents of the heteronorbornadienic systems.
Glucocerebrosidase (GCase) activity modulation by 2-alkyl trihydroxypiperidines: Inhibition and pharmacological chaperoning
(Elsevier, 2020-05) Clemente, F.; Matassini, C.; Faggi, C.; Giachetti, S.; Cresti, C.; Morrone, A.; Paoli, P.; Goti, A.; Martínez Bailén, Macarena; Cardona, F.; Química Orgánica; Fondazione CR Firenze; Ministerio de Economía y Competitividad (MINECO). España
The enzyme glucocerebrosidase (GCase) has become an important therapeutic target due to its involvement in pathological disorders consequent to enzyme deficiency, such as the lysosomal storage Gaucher disease (GD) and the neurological Parkinson disease (PD). Pharmacological chaperones (PCs) are small compounds able to stabilize enzymes when used at sub-inhibitory concentrations, thus rescuing enzyme activity. We report the stereodivergent synthesis of trihydroxypiperidines alkylated at C-2 with both configurations, by means of the stereoselective addition of Grignard reagents to a carbohydrate-derived nitrone in the presence or absence of Lewis acids. All the target compounds behave as good GCase inhibitors, with IC50 in the micromolar range. Moreover, compound 11a behaves as a PC in fibroblasts derived from Gaucher patients bearing the N370/RecNcil mutation and the homozygous L444P mutation, rescuing the activity of the deficient enzyme by up to 1.9- and 1.8-fold, respectively. Rescues of 1.2–1.4-fold were also observed in wild-type fibroblasts, which is important for targeting sporadic forms of PD.
Light-responsive glycosidase inhibitors: Tuning enzyme selectivity and switching factors through integrated chemical and optoglycomic strategies
(Elsevier, 2025-07-15) Rivero Barbarroja, Gonzalo; Maisonneuve, Stéphane; Xie, Juan; García Fernández, José Manuel; Ortiz Mellet, Carmen; Química Orgánica; Ministerio de Ciencia, Innovación y Universidades (MICIU). España
Photopharmacology leverages light-responsive drugs to achieve spatiotemporal control over their activation and interactions with biological targets. This high level of precision is particularly crucial for therapeutic strategies that require sequential drug-target binding and dissociation, such as pharmacological chaperones (PCs) for lysosomal storage disorders (LSDs). PCs must tightly bind misfolded glycosidases in the endoplasmic reticulum (ER) to promote proper folding, yet efficiently dissociate in the lysosome to restore enzymatic function. Here, we demonstrate that azobenzene-equipped, photoswitchable sp2-iminosugars can fulfill these criteria by exploiting differential E-/Z-isomer interactions with aglycone-accommodating regions of target glycosidases. A diversity-oriented strategy was implemented, incorporating variations in glycomimetic portions, linkers, azobenzene substitution patterns, distal substituents, and valency to fine-tune light and temperature responsiveness. This approach yielded derivatives capable of selectively switching between α- and β-glucosidase inhibition, as well as conjugates exhibiting reversible nanomolar inhibition of human glucocerebrosidase, the dysfunctional enzyme in Gaucher disease, with remarkable switching factors under conditions that mirror the scenario at the ER and the lysosome. The results expand the scope of optoglycomics by providing a framework for designing photocommutators that enable reversible glycosidase modulation and laying the foundation for next-generation photoresponsive glycosidase inhibitors with therapeutic potential in LSDs and broader biomedical applications.
Exploring a Novel Anti-Inflammatory Therapy for Diabetic Retinopathy Based on Glyco-Zeolitic-Imidazolate Frameworks
(Multidisciplinary Digital Publishing Institute (MDPI), 2025-06-17) Díaz Paredes, Elena; Martín Loro, Francisco; Rodríguez Marín, Rocío; Gómez Jaramillo, Laura; Sánchez Fernández, Elena Matilde; Carrillo Carrión, Carolina; Arroba, Ana I.; Química Orgánica; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Instituto de Salud Carlos III
Diabetic retinopathy is an ocular disease caused by changes in the expression of inflammatory mediators and increased oxidative stress in the retina and is the leading cause of vision loss in diabetic patients. Currently, there is no treatment capable of reversing retinal damage, which represents a significant burden on the quality of life of patients. (1R)-1-Dodecylsulfonyl-5N,6O-oxomethylidenenojirimycin stands outs as a prototype of the sp2-iminoglycolipids family for its beneficial neuroprotective effect against this chronic eye disease. Critical issues related to the low solubility and bioavailability of this glycolipid in biological settings are overcome by its encapsulation in a Zeolitic-Imidazolate Framework (ZIF) structure, resulting in homogeneous and biocompatible GlycoZIF nanoparticles. Cell studies show an enhanced cellular uptake compared with the free glycolipid, and importantly, its bioactivity is preserved once released inside cells. Methods: Extensive in vitro and ex vivo assays with diabetic retinopathy models unveil the mechanistic pathways of the designed GlycoZIF. Results: A reduction in proinflammatory mediators, increased heme oxygenase-1 level, inhibition of NLRP3 inflammasome, and reduced reactive gliosis is shown. Conclusions: These findings demonstrate for the first time the potential of Glyco-modified ZIFs for the treatment of diabetes-related ocular problems by controlling the immune-mediated inflammatory response.
Multimodal antiproliferative effects of oleanolic acid mitocans: In vitro and in vivo studies
(Elsevier, 2025-04) Puerta, Adrián; González-Bakker, Aday; Romanos, Eduardo; Domínguez García, Inmaculada; Martínez Montiel, Mónica; Merino-Montiel, Penélope; Fernández-Bolaños Guzmán, José María; López López, Óscar; Padrón, José M.; Química Orgánica; Ministerio de Ciencia e Innovación (MICIN). España; Agencia Estatal de Investigación. España; European Union (UE); Junta de Andalucía
Mitochondria-targeting drugs (mitocans) based on organic cations are emerging as powerful and selective cancer,therapeutics. In this study, we have evaluated a novel series of oleanolic acid-derived mitocans, revealing,nanomolar-range antiproliferative effects against human solid tumor cells. Continuous live-cell imaging revealed,extensive cytoplasmic vacuolation, while mechanistic studies identified paraptosis as the dominant form of cell,death. Remarkably, in vivo experiments demonstrated significant tumor growth inhibition in mice, with no,detectable toxicity at therapeutic doses. These findings highlight the potential of oleanolic acid-derived mitocans,as promising candidates for cancer therapy.
β-Cyclodextrin-based geometrically frustrated amphiphiles as one-component, cell-specific and organ-specific nucleic acid delivery systems
(Elsevier, 2025-01-01) Rivero Barbarroja, Gonzalo; López Fernández, José; Juárez Gonzálvez, Inmaculada; Fernández Clavero, C.; Di Giorgio, Christophe; Vélaz, Itziar; Ortiz Mellet, Carmen; García Fernández, José M.; Química Orgánica; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Agencia Estatal de Investigación. España; European Union (UE)
We introduce an innovative β-cyclodextrin (βCD)-prototype for delivering nucleic acids: “geometrically frustrated amphiphiles (GFAs).” GFAs are designed with cationic centers evenly distributed across the primary O6 and secondary O2 positions of the βCD scaffold, while hydrophobic tails are anchored at the seven O3 positions. Such distribution of functional elements differs from Janus-type architectures and enlarges the capacity for accessing strictly monodisperse variants. Changes at the molecular level can then be correlated with preferred self-assembly and plasmid DNA (pDNA) co-assembly behaviors. Specifically, GFAs undergo pH-dependent transition between bilayered to monolayered vesicles or individual molecules. GFA-pDNA nanocomplexes exhibit topological and internal order characteristics that are also a function of the GFA molecular architecture. Notably, adjusting the pKa of the cationic heads and the hydrophilic-hydrophobic balance, pupa-like arrangements implying axial alignments of GFA units flanked by quasi-parallel pDNA segments are preferred. In vitro cell transfection studies revealed remarkable differences in relative performances, which corresponded to distinct organ targeting outcomes in vivo. This allowed for preferential delivery to the liver and lung, kidney or spleen. The results collectively highlight cyclodextrin-based GFAs as a promising class of molecular vectors capable of finely tuning cell and organ transfection selectivity
STD NMR Epitope Perturbation by Mutation Unveils the Mechanismof YM155 as an Arginine-Glycosyltransferases Inhibitor Effective inTreating Enteropathogenic Diseases
(American Chemical Society, 2025-03) Ramírez Cárdenas, Jonathan; Taleb, Víctor; Calvaresi, Valeria; Struwe, WB; El Qaidi, Samir; Zhu, Congrui; Muñoz García, Juan Carlos; Angulo Álvarez, Jesús; Química Orgánica; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Agencia Estatal de Investigación. España; European Union (UE); Gobierno de Aragón
Enteropathogenic arginine-glycosyltransferases(Arg-GTs) alter higher eukaryotic proteins by attaching a GlcNAcresidue to arginine acceptor sites, disrupting essential pathwayssuch as NF-κB signaling, which promotes bacterial survival. Theseenzymes are potential drug targets for treating related diseases. Inthis study, we present a novel STD NMR Epitope Perturbation byMutation spectroscopic approach that, in combination withhydrogen−deuterium exchange mass spectrometry (HDX-MS),and molecular dynamics simulations, shows that the highly potentbroad-spectrum anticancer drug YM155 serves as a potentialnoncompetitive inhibitor of these enzymes. It induces aconformation of the arginine acceptor site unfavorable for GlcNActransfer, which underlies the molecular mechanism by which thiscompound exerts its inhibitory function. Finally, we also demonstrate that YM155 effectively treats enteropathogenic diseases in amouse model, highlighting its therapeutic potential. Overall, our data suggest that this compound can be repurposed to not only treatcancer but also infectious diseases.
Light-controlled assembly and disassembly of cyclodextrin-bisazobenzene supramolecular complexes
(Elsevier, 2025-04-16) Fernández Clavero, Carlos; Rivero Barbarroja, Gonzalo; Carmona, Thais; García Iriepa, C.; Marcelo, Gema; Tros de Ilarduya, Conchita; Ortiz Mellet, Carmen; García Fernández, José M.; Benito, Juan M.; Mendicuti, Francisco; Química Orgánica; Ministerio de Ciencia, Innovación y Universidades (MICINN). España; Agencia Estatal de Investigación. España; European Union (UE); Universidad de Alcalá
The inclusion complexation of a water soluble bis-azobenzene derivative (bis-Azo) and its monotopic analog (mono-Azo) with α-, β-, and γ-cyclodextrins (CyDs) was investigated as a prototype for light-responsive selfassembling systems. Using spectroscopic techniques (UV–vis, induced circular dichroism, 1 H NMR), computational methods (molecular mechanics and dynamics), and thermodynamic analyses, we examined the photoswitching properties, stability, and structural dynamics of these systems. The azobenzene moieties in the Eisomer of mono-Azo and bis-Azo consistently showed strong affinity for the αCyD cavity, characterized by high association constants. In contrast, no complex formation was observed upon photoinduced E-to-Z isomerization. For bis-Azo, this implies the formation of supramolecular αCyD dimers, with the spatial separation between the oppositely oriented host components determined by the connector linking the two azobenzene moieties in the Econfigured ditopic guest. This complex disassembles upon photoswitching, driven by the structural disruption associated with the Z-form. Both the E-and Z-isomers fitted in the cavity of βCyD, with moderate selectivity towards the E-form. A similar scenario was found for complexes with γCyD when using low concentrations of the host. Interestingly, at high concentrations γCyD formed low-solubility pseudopolyrotaxane-type supramolecular architectures with bis-Azo, which were disrupted upon Z-isomer photoisomerization. All the complexes demonstrated high fatigue resistance, maintaining structural integrity after multiple isomerization cycles. This work advances the design of stimuli-responsive preorganized supramolecular systems, with potential applications in nucleic acid delivery through dual pH/light-sensitive mechanisms.
An isofagomine analogue with an amidine group inthe 1,6-position
(Royal Society Open Science, 2024-02) Vaaland, I. Caroline; Christensen, Idd Andrea; Pejov, Ljupcho; Morén, Monika; Westlund, Nikolai; Santos Evangelista, Tereza C.; Sydnes, Magne O.; Aachmann, Finn L.; López López, Óscar; Lindbäck, Emil; Química Inorgánica; Ministerio de Ciencia, Innovación y Universidades (MICINN). España; Agencia Estatal de Investigación. España; Junta de Andalucía
The synthesis of an isofagomine analogue with an amidine group in the 1,6-position is described. Density functional theory calculations showed that this compound has a remarkably different charge distribution compared with isofagomine. This may explain why the amidine is a poor glycosidase inhibitor (IC50 > 50 µM against all tested enzymes) compared with isofagomine.
Hydrogels and Nanogels: Pioneering the Future of Advanced Drug Delivery Systems
(Multidisciplinary Digital Publishing Institute (MDPI), 2025-02-07) Delgado-Pujol, Ernesto J.; Martínez Muñoz, Guillermo; Casado Jurado, David; Vázquez Cabello, Juan; León Barberena, Jesús; Rodríguez Lucena, David; Torres Hernández, Yadir; Alcudia Cruz, Ana; Begines Ruiz, Belén; Química Orgánica y Farmacéutica; Ingeniería y Ciencia de los Materiales y del Transporte; Química Orgánica; Ministerio de Ciencia, Innovación y Universidades (MICIU). España
Conventional drug delivery approaches, including tablets and capsules, often suffer from reduced therapeutic effectiveness, largely attributed to inadequate bioavailability and difficulties in ensuring patient adherence. These challenges have driven the development of advanced drug delivery systems (DDS), with hydrogels and especially nanogels emerging as promising materials to overcome these limitations. Hydrogels, with their biocompatibility, high water content, and stimuli-responsive properties, provide controlled and targeted drug release. This review explores the evolution, properties, and classifications of hydrogels versus nanogels and their applications in drug delivery, detailing synthesis methods, including chemical crosslinking, physical self-assembly, and advanced techniques such as microfluidics and 3D printing. It also examines drug-loading mechanisms (e.g., physical encapsulation and electrostatic interactions) and release strategies (e.g., diffusion, stimuli-responsive, and enzyme-triggered). These gels demonstrate significant advantages in addressing the limitations of traditional DDS, offering improved drug stability, sustained release, and high specificity. Their adaptability extends to various routes of administration, including topical, oral, and injectable forms, while emerging nanogels further enhance therapeutic targeting through nanoscale precision and stimuli responsiveness. Although hydrogels and nanogels have transformative potential in personalized medicine, challenges remain in scalable manufacturing, regulatory approval, and targeted delivery. Future strategies include integrating biosensors for real-time monitoring, developing dual-stimuli-responsive systems, and optimizing surface functionalization for specificity. These advancements aim to establish hydrogels and nanogels as cornerstones of next-generation therapeutic solutions, revolutionizing drug delivery, and paving the way for innovative, patient-centered treatments.
Exploring the Chemistry and Applications of Thio-, Seleno-, and Tellurosugars
(Multidisciplinary Digital Publishing Institute (MDPI), 2025-05-05) Martínez Pascual, Roxana; Valera Zaragoza, Mario; Fernández-Bolaños Guzmán, José María; López López, Óscar; Química Orgánica; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Junta de Andalucía
Given the crucial roles of carbohydrates in energy supply, biochemical processes, signaling events and the pathogenesis of several diseases, the development of carbohydrate analogues, called glycomimetics, is a key research area in Glycobiology, Pharmacology, and Medicinal Chemistry. Among the many structural transformations explored, the replacement of endo- and exocyclic oxygen atoms by carbon (carbasugars) or heteroatoms, such as nitrogen (aza- and iminosugars), phosphorous (phosphasugars), sulfur (thiosugars), selenium (selenosugars) or tellurium (tellurosugars) have garnered significant attention. These isosteric substitutions can modulate the carbohydrate bioavailability, stability, and bioactivity, while introducing new properties, such as redox activity, interactions with pathological lectins and enzymes, or cytotoxic effects. In this manuscript we have focused on three major families of glycomimetics: thio-, seleno-, and tellurosugars. We provide a comprehensive review of the most relevant synthetic pathways leading to substitutions primarily at the endocyclic and glycosidic positions. The scope includes metal-catalyzed reactions, organocatalysis, electro- and photochemical transformations, free-radical processes, and automated syntheses. Additionally, mechanistic insights, stereoselectivity, and biological properties are also discussed. The structural diversity and promising bioactivities of these glycomimetics underscore their significance in this research area.
Fluorinated Man9 as a High Mannose Mimetic to Unravel Its Recognition by DC-SIGN Using NMR
(American Chemical Society, 2023-11-08) Silva Díaz, Adrián; Ramírez Cárdenas, Jonathan; Muñoz García, Juan Carlos; de la Fuente, M. Carmen; Thépaut, Michel; Fieschi, Franck; Ramos Soriano, Javier; Angulo Álvarez, Jesús; Rojo, Javier; Química Orgánica; Ministerio de Ciencia e Innovación (MICIN). España; Agencia Estatal de Investigación. España; European Union (UE)
Lectins are capable of reading out the structural information contained in carbohydrates through specific recognition processes. Determining the binding epitope of the sugar is fundamental to understanding this recognition event. Nuclear magnetic resonance (NMR) is a powerful tool to obtain this structural information in solution; however, when the sugar involved is a complex oligosaccharide, such as high mannose, the signal overlap found in the NMR spectra precludes an accurate analysis of the interaction. The introduction of tags into these complex oligosaccharides could overcome these problems and facilitate NMR studies. Here, we show the preparation of the Man9 of high mannose with some fluorine tags and the study of the interaction with its receptor, dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN). This fluorinated ligand has allowed us to apply heteronuclear two-dimensional (2D) 1H,19F STD-TOCSYreF NMR experiments, using the initial slope approach, which has facilitated the analysis of the Man9/DC-SIGN interaction, unequivocally providing the binding epitope.
Rational Design of Dual-Domain Binding Inhibitors for N-Acetylgalactosamine Transferase 2 with Improved Selectivity over the T1 and T3 Isoforms
(American Chemical Society, 2024-09-11) Compañón, Ismael; Ballard, Collin J.; Lira Navarrete, Enardi; Santos, Tanausú; Monaco, Serena; Muñoz García, Juan Carlos; Angulo Álvarez, Jesús; Ghirardello, Mattía; Química Orgánica; Agencia Estatal de Investigación. España; Universidad de La Rioja; Gobierno de Aragón; European Union (UE)
The GalNAc-transferase (GalNAc-T) family, consisting of 20 isoenzymes, regulates the O-glycosylation process of mucin glycopeptides by transferring GalNAc units to serine/threonine residues. Dysregulation of specific GalNAc-Ts is associated with various diseases, making these enzymes attractive targets for drug development. The development of inhibitors is key to understanding the implications of GalNAc-Ts in human diseases. However, developing selective inhibitors for individual GalNAc-Ts represents a major challenge due to shared structural similarities among the isoenzymes and some degree of redundancy among the natural substrates. Herein, we report the development of a GalNAc-T2 inhibitor with higher potency compared to those of the T1 and T3 isoforms. The most promising candidate features bivalent GalNAc and thiophene moieties on a peptide chain, enabling binding to both the lectin and catalytic domains of the enzyme. The binding mode was confirmed by competitive saturation transfer difference NMR experiments and validated through molecular dynamics simulations. The inhibitor demonstrated an IC50 of 21.4 μM for GalNAc-T2, with 8- and 32-fold higher selectivity over the T3 and T1 isoforms, respectively, representing a significant step forward in the synthesis of specific GalNAc-T inhibitors tailored to the unique structural features of the targeted isoform.
Fluorinated trehalose analogues for cell surface engineering and imaging of Mycobacterium tuberculosis
(2024-08-12) Guy, Collette S.; Gott, James A.; Ramírez Cárdenas, Jonathan; de Wolf, Cristopher; Furze, Christopher M.; West, Geoff; Muñoz García, Juan Carlos; Angulo Álvarez, Jesús; Fullam, Elizabeth; Química Orgánica; Ministerio de Ciencia e Innovación (MICIN). España; Agencia Estatal de Investigación. España; European Union (UE)
The sensitive, rapid and accurate diagnosis of Mycobacterium tuberculosis (Mtb) infection is a central challenge in controlling the global tuberculosis (TB) pandemic. Yet the detection of mycobacteria is often made difficult by the low sensitivity of current diagnostic tools, with over 3.6 million TB cases missed each year. To overcome these limitations there is an urgent need for next-generation TB diagnostic technologies. Here we report the use of a discrete panel of native 19F-trehalose (F-Tre) analogues to label and directly visualise Mtb by exploiting the uptake of fluorine-modified trehalose analogues via the mycobacterial trehalose LpqY-SugABC ATP-binding cassette (ABC) importer. We discovered the extent of modified F-Tre uptake correlates with LpqY substrate recognition and characterisation of the interacting sites by saturation transfer difference NMR coupled with molecular dynamics provides a unique glimpse into the molecular basis of fluorine-modified trehalose import in Mtb. Lipid profiling demonstrated that F-Tre analogues modified at positions 2, 3 and 6 are incorporated into mycobacterial cell-surface trehalose-containing glycolipids. This rapid one-step labelling approach facilitates the direct visualisation of F-Tre-labelled Mtb by Focused Ion Beam (FIB) Secondary Ion Mass Spectrometry (SIMS), enabling detection of the Mtb pathogen. Collectively, our findings highlight that F-Tre analogues have potential as tools to probe and unravel Mtb biology and can be exploited to detect and image TB.
Fast Quantitative Validation of 3D Models of Low-Affinity Protein-Ligand Complexes by STD NMR Spectroscopy
(American Chemical Society, 2024-06-07) Nepravishta, Ridvan; Ramírez Cárdenas, Jonathan; Rocha, Gabriel; Walpole, Samuel; Hicks, Thomas; Monaco, Serena; Muñoz García, Juan Carlos; Angulo Álvarez, Jesús; Química Orgánica; Biotechnology and Biological Sciences Research Council (BBSRC). U. K.; Agencia Estatal de Investigación. España; Ministerio de Ciencia e Innovación (MICIN). España; European Union (UE)
Low-affinity protein–ligand interactions are important for many biological processes, including cell communication, signal transduction, and immune responses. Structural characterization of these complexes is also critical for the development of new drugs through fragment-based drug discovery (FBDD), but it is challenging due to the low affinity of fragments for the binding site. Saturation transfer difference (STD) NMR spectroscopy has revolutionized the study of low-affinity receptor–ligand interactions enabling binding detection and structural characterization. Comparison of relaxation and exchange matrix calculations with 1H STD NMR experimental data is essential for the validation of 3D structures of protein–ligand complexes. In this work, we present a new approach based on the calculation of a reduced relaxation matrix, in combination with funnel metadynamics MD simulations, that allows a very fast generation of experimentally STD-NMR-validated 3D structures of low-affinity protein–ligand complexes.
Differential Solvent DEEP-STD NMR and MD Simulations Enable the Determinants of the Molecular Recognition of Heparin Oligosaccharides by Antithrombin to Be Disentangled
(MDPI, 2024-04-26) Parafioriti, Michela; Elli, Stefano; Muñoz García, Juan Carlos; Ramírez Cárdenas, Jonathan; Yates, Edwin A.; Angulo Álvarez, Jesús; Guerrini, Marco; Química Orgánica; Fundación G. Ronzoni. Italia; Ministerio de Ciencia e Innovación (MICIN). España; Agencia Estatal de Investigación. España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)
The interaction of heparin with antithrombin (AT) involves a specific sequence corresponding to the pentasaccharide GlcNAc/NS6S-GlcA-GlcNS3S6S-IdoA2S-GlcNS6S (AGA*IA). Recent studies have revealed that two AGA*IA-containing hexasaccharides, which differ in the sulfation degree of the iduronic acid unit, exhibit similar binding to AT, albeit with different affinities. However, the lack of experimental data concerning the molecular contacts between these ligands and the amino acids within the protein-binding site prevents a detailed description of the complexes. Differential epitope mapping (DEEP)-STD NMR, in combination with MD simulations, enables the experimental observation and comparison of two heparin pentasaccharides interacting with AT, revealing slightly different bound orientations and distinct affinities of both glycans for AT. We demonstrate the effectiveness of the differential solvent DEEP-STD NMR approach in determining the presence of polar residues in the recognition sites of glycosaminoglycan-binding proteins.
Organocatalytic Applications of Sulfonyl Squaramides in Anion-Recognition Strategies
(Willey, 2024-10-16) Benítez Narváez, Manuel; Matador Martínez, Esteban; Velázquez Muñoz, Marta; Lassaletta, José M.; Fernández Fernández, Rosario Fátima; Monge Fernández, David; Química Orgánica; Ministerio de Ciencia e Innovación (MICIN). España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Junta de Andalucía
A modular, 3-steps protocol for the synthesis of N-sulfonyl squaramides has been developed. The strategic installation of a tetrahedral, electron-withdrawing sulfonyl group into the squaramido core allowed the prevention of undesired self-aggregations, therefore upgrading the solubility in common organic solvents, and moreover, enhancing their H-bond donor abilities for molecular recognition. These unique features have been efficiently exploited in two different ion-pairing reactions: (i) the challenging C4-selective dearomatization of 2-picoline with silyl ketene acetals and (ii) the tritylation of N-methylindole. Furthermore, their catalytic activities have been directly compared with other common and well-established (thio)urea analogues and related H-bond donors, revealing that highly acidic designs are essential to reach optimal catalytic performances.

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