zur Suche springenzur Navigation springenzum Inhalt springen

Sortieren nach: Erscheinungsjahr Typ der Publikation

Zeige Ergebnisse 1 bis 10 von 51.

Publikation

Méndez, Y.; Vasco, A. V.; Ebensen, T.; Schulze, K.; Yousefi, M.; Davari, M. D.; Wessjohann, L. A.; Guzmán, C. A.; Rivera, D. G.; Westermann, B.; Diversification of a novel α‐galactosyl ceramide hotspot boosts the adjuvant properties in parenteral and mucosal vaccines Angew. Chem. Int. Ed. 63, e202310983, (2024) DOI: 10.1002/anie.202310983

The development of potent adjuvants is an important step for improving the performance of subunit vaccines. CD1d agonists, such as the prototypical α‐galactosyl ceramide (α‐GalCer), are of special interest due to their ability to activate iNKT cells and trigger rapid dendritic cell maturation and B‐cell activation. Herein, we introduce a novel derivatization hotspot at the α‐GalCer skeleton, namely the N‐substituent at the amide bond. The multicomponent diversification of this previously unexplored glycolipid chemotype space permitted the introduction of a variety of extra functionalities that can either potentiate the adjuvant properties or serve as handles for further conjugation to antigens toward the development of self‐adjuvanting vaccines. This strategy led to the discovery of compounds eliciting enhanced antigen‐specific T cell stimulation and a higher antibody response when delivered by either the parenteral or the mucosal route, as compared to a known potent CD1d agonist. Notably, various functionalized α‐GalCer analogues showed a more potent adjuvant effect after intranasal immunization than a PEGylated α‐GalCer analogue previously optimized for this purpose. Ultimately, this work could open multiple avenues of opportunity for the use of mucosal vaccines against microbial infections.
Publikation

Hernández, G.; Ramos, B.; Sultani, H. N.; Ortiz, Y.; Spengler, I.; Castañeda, R. F.; Rivera, D. G.; Arnold, N.; Westermann, B.; Mirabal, Y.; Cultural characterization and antagonistic activity of Cladobotryum virescens against some phytopathogenic fungi and oomycetes Agronomy 13, 389, (2023) DOI: 10.3390/agronomy13020389

In this study, the characteristic growth of Cladobotryum virescens on nine culture media was analyzed. The growing behavior of this fungus was dependent on the culture medium. In vitro analysis showed that oat agar was better than other media tested with the highest conidia production. The antifungal activity against Fusarium chlamydosporum and Alternaria brassicicola was evaluated by the Dual Culture method. C. virescens displayed high activity against both pathogens acting through antibiosis and mycoparasitism. This effect was increased by a higher competitiveness of the strain for the substrate. Furthermore, the crude ethyl acetate extract of the culture broth was tested in vitro against Botrytis cinerea and Septoria tritici, as well as the hemibiotrophic oomycete Phytophthora infestans using a microtiter plate assay at different concentrations. The extract showed excellent inhibition even below 5 ppm. According to these results, we concluded that C. virescens can be considered as a potential biological control agent in agriculture. To the best of our knowledge, this is the first study to investigate C. virescens as a biocontrol agent for different diseases caused by five relevant pathogens that affect cereals and vegetables.
Publikation

Vasco, A. V.; Méndez, Y.; González, C.; Pérez, C. S.; Reguera, L.; Wessjohann, L. A.; Rivera, D. G.; Advancing multicomponent strategies to macrobicyclic peptides ChemBioChem 24, e202300229, (2023) DOI: 10.1002/cbic.202300229

Macrocyclization of peptides is typically used to fix specific bioactive conformations and improve their pharmacological properties. Recently, macrobicyclic peptides have received special attention owing to their capacity to mimic protein structures or be key components of peptide-drug conjugates. Here, we describe the development of novel synthetic strategies for two distinctive types of peptide macrobicycles. A multicomponent macrocyclo-dimerization approach is introduced for the production of interconnected β-turns, allowing two macrocyclic rings to be formed and dimerized in one pot. Also, an on-resin double stapling strategy is described for the assembly of lactam-bridged macrobicycles with stable tertiary folds.
Publikation

Vasco, A. V.; Ceballos, L. G.; Wessjohann, L. A.; Rivera, D. G.; Multicomponent functionalization of the octreotide peptide macrocyclic scaffold Eur. J. Org. Chem. 2022, e202200687, (2022) DOI: 10.1002/ejoc.202200687

The replacement of the disulfide bridge by other types of side chain linkages has been a continuous endeavor in the development of cyclic peptide drugs with improved metabolic stability. Octreotide is a potent and selective somatostatin analog that has been used as an anticancer agent, in radiolabeled conjugates for the localization of tumors and as targeting moiety in peptide-drug conjugates. Here, we describe an onresin methodology based on a multicomponent macrocyclization that enables the substitution of the disulfide bond by a tertiary lactam bridge functionalized with a variety of exocyclic moieties, including lipids, fluorophores, and charged groups. Conformational analysis in comparison with octreotide provides key information on the type of functionalization permitting the conformational mimicry of the bioactive peptide.
Publikation

Humpierre, A. R.; Zanuy, A.; Saenz, M.; Vasco, A. V.; Méndez, Y.; Westermann, B.; Cardoso, F.; Quintero, L.; Santana, D.; Verez, V.; Valdés, Y.; Rivera, D. G.; Garrido, R.; Quantitative NMR for the structural analysis of novel bivalent glycoconjugates as vaccine candidates J. Pharm. Biomed. Anal. 214, 114721, (2022) DOI: 10.1016/j.jpba.2022.114721

Novel unimolecular bivalent glycoconjugates were assembled combining several functionalized capsular polysaccharides of Streptococcus pneumoniae and Neisseria meningitidis to a carrier protein by using an effective strategy based on the Ugi 4-component reaction. The development of multivalent glycoconjugates opens new opportunities in the field of vaccine design, but their high structural complexity involves new analytical challenges. Nuclear Magnetic Resonance has found wide applications in the characterization and impurity profiling of carbohydrate-based vaccines. Eight bivalent conjugates were studied by quantitative NMR analyzing the structural identity, the content of each capsular polysaccharide, the ratios between polysaccharides, the polysaccharide to protein ratios and undesirable contaminants. The qNMR technique involves experiments with several modified parameters for obtaining spectra with quantifiable signals. In addition, the achieved NMR results were combined with the results of colorimetric assay and Size Exclusion HPLC for assessing the protein content and free protein percentage, respectively. The application of quantitative NMR showed to be efficient to clear up the new structural complexities while allowing the quantitative assessment of the components.
Publikation

González-Bacerio, J.; Varela, A. C.; Aguado, M. E.; Izquierdo, M.; Méndez, Y.; del Rivero, M. A.; Rivera, D. G.; Bacterial metalo-aminopeptidases as targets in human infectious diseases Current Drug Targets 23, 1155-1190, (2022) DOI: 10.2174/1389450123666220316085859

Background: Human infectious diseases caused by bacteria are a worldwide health problem due to the increased resistance of these microorganisms to conventional antibiotics. For this reason, the identification of novel molecular targets and the discovery of new antibacterial compounds is urgently required. Metalo-aminopeptidases are promising targets in bacterial infections. They participate in crucial processes for bacterial growth and pathogenesis, such as protein and peptide degradation to supply amino acids, protein processing, access to host tissues, cysteine supply for redox control, transcriptional regulation, site-specific DNA recombination, and hydrogen sulfide production. Although several of these enzymes are not essential, they are required for virulence and maximal growth in conditions of nutrient limitation and high temperatures.Objective: In this review, we describe the structural, functional and kinetic properties of some examples of bacterial metalo-aminopeptidases, in the context of their use as antibacterial targets. In addition, we present some inhibitors reported for these enzymes.Conclusion: It is necessary a meticulous work to validate these peptidases as good/bad targets and to identify inhibitors with a potential therapeutic use.
Bücher und Buchkapitel

Vasco, A. V.; Ricardo, M. G.; Rivera, D. G.; Wessjohann, L. A.; Ligation, Macrocyclization, and Simultaneous Functionalization of Peptides by Multicomponent Reactions (MCR) Methods Mol. Biol. 2371, 143-157, (2022) ISBN: 978-1-0716-1688-8 DOI: 10.1007/978-1-0716-1689-5_8

Multicomponent reactions (MCRs) are recently expanding the plethora of solid-phase protocols for the synthesis and derivatization of peptides. Herein, we describe a solid-phase-compatible strategy based on MCRs as a powerful strategy for peptide cyclization and ligation . We illustrate, using Gramicidin S as a model peptide, how the execution of on-resin Ugi reactions enables the simultaneous backbone N-functionalization and cyclization, which are important types of derivatizations in peptide-based drug development or for incorporation of conjugation handles, or labels.
Publikation

Rivera, D. G.; Ricardo, M. G.; Vasco, A. V.; Wessjohann, L. A.; Van der Eycken, E. V.; On-resin multicomponent protocols for biopolymer assembly and derivatization Nat. Protoc. 16, 561-578, (2021) DOI: 10.1038/s41596-020-00445-6

Solid-phase synthesis represents the methodological showcase for technological advances such as split-and-pool combinatorial chemistry and the automated synthesis of peptides, nucleic acids and polysaccharides. These strategies involve iterative coupling cycles that do not generate functional diversity besides that incorporated by the amino acids, nucleosides and monosaccharide building blocks. In sharp contrast, multicomponent reactions (MCRs) are traditionally used to generate both skeletal and appendage diversity in short, batchwise procedures. On-resin MCRs have traditionally been employed for the construction of heterocycle and peptidomimetic libraries, but that scenario has changed recently, and today the focus is more on the solid-phase derivatization of peptides and oligonucleotides. This review presents relevant experimental details and addresses the synthetic scope of such on-resin multicomponent protocols employed to accomplish specific biopolymer covalent modifications that are practically inviable by traditional solution-phase methodologies. Recommendations are provided to facilitate the implementation of solid-supported protocols and avoid possible pitfalls associated with the selection of the polymeric resin, the solvent and the order and amount of the reagents employed. We describe procedures comprising the multicomponent lipidation, biotinylation and labeling of both termini and the side chains, as well as the use of MCRs in the traceless on-resin synthesis of ligated and cyclic peptides. Solid-phase protocols for the assembly of α-helical and parallel β-sheet peptides as well as hybrid peptide–peptoid and peptide–peptide nucleic acid architectures are described. Finally, the solid-supported multicomponent derivatization of DNA oligonucleotides is illustrated as part of the DNA-encoded library technology relying on MCR-derived heterocyclic compounds.
Publikation

Ricardo, M. G.; Vázquéz-Mena, Y.; Iglesias-Morales, Y.; Wessjohann, L. A.; Rivera, D. G.; On the scope of the double Ugi multicomponent stapling to produce helical peptides Bioorg. Chem. 113, 104987, (2021) DOI: 10.1016/j.bioorg.2021.104987

The stabilization of helical structures by peptide stapling approaches is now a mature technology capable to provide a variety of biomedical applications. Recently, it was shown that multicomponent macrocyclization is not only an effective way to introduce conformational constraints but it also allows to incorporate additional functionalities to the staple moiety in a one-pot process. This work investigates the scope of the double Ugi multicomponent stapling approach in its capacity to produce helical peptides from unstructured sequences. For this, three different stapling combinations were implemented and the CD spectra of the cyclic peptides were measured to determine the effect of the multicomponent macrocyclization on the resulting secondary structure. A new insight into some structural factors influencing the helicity type and content is provided, along with new prospects on the utilization of this methodology to diversify the molecular tethers linking the amino acid side chains.
Publikation

Vasco, A. V.; Brode, M.; Méndez, Y.; Valdés, O.; Rivera, D. G.; Wessjohann, L. A.; Synthesis of Lactam-Bridged and Lipidated Cyclo-Peptides as Promising Anti-Phytopathogenic Agents Molecules 25, 811, (2020) DOI: 10.3390/molecules25040811

Antimicrobial resistance to conventional antibiotics and the limited alternatives to combat plant-threatening pathogens are worldwide problems. Antibiotic lipopeptides exert remarkable membrane activity, which usually is not prone to fast resistance formation, and often show organism-type selectivity. Additional modes of action commonly complement the bioactivity profiles of such compounds. The present work describes a multicomponent-based methodology for the synthesis of cyclic polycationic lipopeptides with stabilized helical structures. The protocol comprises an on solid support Ugi-4-component macrocyclization in the presence of a lipidic isocyanide. Circular dichroism was employed to study the influence of both macrocyclization and lipidation on the amphiphilic helical structure in water and micellar media. First bioactivity studies against model phytopathogens demonstrated a positive effect of the lipidation on the antimicrobial activity.
IPB Mainnav Search