20 results on '"Yanira Méndez"'
Search Results
2. Nuevos inhibidores de metaloaminopeptidasas M1 microbianas obtenidos mediante síntesis química
- Author
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Jorge González Bacerio, Yanira Méndez Gómez, Daniel García Rivera, Maday Alonso del Rivero Antigua, Marcos Gazarini Dutra, María de los Á. Chávez Planes, and Adriana K. Carmona
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agentes antibacterianos y antimaláricos ,aminopeptidasas m1 microbianas ,inhibidores sintéticos de aminopeptidasas ,reacción de ugi multicomponente ,Science ,Science (General) ,Q1-390 - Abstract
Introducción. Las infecciones por bacterias resistentes a los antibióticos convencionales constituyen un problema de salud mundial. Igualmente, el parásito causante de la malaria, principal enfermedad parasitaria tropical, ha desarrollado resistencia a los medicamentos tradicionales. En este sentido, las aminopeptidasas ePepN, de la bacteriaEscherichia coli, y PfA-M1, del parásito Plasmodium falciparum, constituyen nuevos blancos en estas enfermedades. El objetivo de este trabajo fue la identificación de inhibidores sintéticos de ePepN y PfA-M1, con potencialidades como agentes antibacterianos y antimaláricos. Métodos. Mediante dos reacciones multicomponentes de Ugi se sintetizaron dos bibliotecas de 33 peptidomiméticos basados en la bestatina y la actinonina, y se evaluaron frente a PfA-M1. Además, se sintetizaron 22 peptidomiméticos tetrazoles, los cuales se evaluaron frente a ePepN. Resultados. Frente a esta enzima, se identificaron 3 tetrazoles (YTE003, YTE007 y YTE008) como inhibidores potentes y selectivos de ePepN, en comparación con la aminopeptidasa M1 porcina (APNp). El YTE003 presenta actividad antibacteriana in vitro, lo que refuerza sus potencialidades como compuesto líder en el campo de los agentes antibacterianos. Frente a PfA-M1, se identificó el compuesto KBE009 como un inhibidor potente, con actividad antimalárica in vitro, que no inhibe a la APNp a concentraciones de relevancia terapéutica, y no es citotóxico hasta 200 µmol/L frente a la línea de células humanas HUVEC. Se comprobó que el KBE009 inhibe la actividad aminopeptidasa en el parásito íntegro y aislado en el mismo orden de magnitud que su actividad antimalárica in vitro. Estas propiedades permiten considerar al peptidomimético una molécula promisoria como compuesto líder contra la malaria.
- Published
- 2020
3. KBE009: A Bestatin-Like Inhibitor of the Trypanosoma cruzi Acidic M17 Aminopeptidase with In Vitro Anti-Trypanosomal Activity
- Author
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Jorge González-Bacerio, Irina Arocha, Mirtha Elisa Aguado, Yanira Méndez, Sabrina Marsiccobetre, Maikel Izquierdo, Daniel G. Rivera, Katherine Figarella, and Néstor L. Uzcátegui
- Subjects
bestatin-like peptidomimetics ,chemotherapy ,leucyl-aminopeptidase ,protease inhibitors ,Trypanosoma cruzi ,Science - Abstract
Chagas disease, caused by the kinetoplastid parasite Trypanosoma cruzi, is a human tropical illness mainly present in Latin America. The therapies available against this disease are far from ideal. Proteases from pathogenic protozoan have been considered as good drug target candidates. T. cruzi acidic M17 leucyl-aminopeptidase (TcLAP) mediates the major parasite’s leucyl-aminopeptidase activity and is expressed in all parasite stages. Here, we report the inhibition of TcLAP (IC50 = 66.0 ± 13.5 µM) by the bestatin-like peptidomimetic KBE009. This molecule also inhibited the proliferation of T. cruzi epimastigotes in vitro (EC50 = 28.1 ± 1.9 µM) and showed selectivity for the parasite over human dermal fibroblasts (selectivity index: 4.9). Further insight into the specific effect of KBE009 on T. cruzi was provided by docking simulation using the crystal structure of TcLAP and a modeled human orthologous, hLAP3. The TcLAP-KBE009 complex is more stable than its hLAP3 counterpart. KBE009 adopted a better geometrical shape to fit into the active site of TcLAP than that of hLAP3. The drug-likeness and lead-likeness in silico parameters of KBE009 are satisfactory. Altogether, our results provide an initial insight into KBE009 as a promising starting point compound for the rational design of drugs through further optimization.
- Published
- 2021
- Full Text
- View/download PDF
4. Synthesis of Lactam-Bridged and Lipidated Cyclo-Peptides as Promising Anti-Phytopathogenic Agents
- Author
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Aldrin V. Vasco, Martina Brode, Yanira Méndez, Oscar Valdés, Daniel G. Rivera, and Ludger A. Wessjohann
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peptide cyclization ,antimicrobial peptides (amps) ,multicomponent reactions (mcrs) ,lipopeptides ,fungicides ,antimycotics ,plant pathogens ,Organic chemistry ,QD241-441 - Abstract
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.
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- 2020
- Full Text
- View/download PDF
5. Repercusión social de la halitosis
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Bárbara Olaydis Hechavarría Martínez, Ruth Ramón Jiménez, and Yanira Méndez Nápoles
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halitosis ,aliento ,enjuague bucal ,higiene bucal ,Medicine (General) ,R5-920 ,Internal medicine ,RC31-1245 - Abstract
La halitosis es un motivo de consulta frecuente al que se enfrenta el médico en la atención primaria. Es un síntoma de múltiples enfermedades estomatológicas, pero se debe plantear un diagnóstico diferencial con otras afecciones (extrabucales, sistémicas y psicológicas), que también la ocasionan. Además de las medidas generales sintomáticas (higiene bucal), también se indica un tratamiento específico según la causa de esta. Teniendo en cuenta las repercusiones sociales, económicas y sanitarias que implica, se exponen algunos aspectos generales sobre el tema
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- 2014
6. Parasite Metalo-aminopeptidases as Targets in Human Infectious Diseases
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Jorge González-Bacerio, Mirtha Elisa Aguado, Maikel Izquierdo, Maikel González-Matos, Ana C. Varela, Yanira Méndez, Maday Alonso del Rivero, and Daniel G. Rivera
- Subjects
Pharmacology ,Clinical Biochemistry ,Drug Discovery ,Molecular Medicine - Abstract
Background: Parasitic human infectious diseases are a worldwide health problem due to the increased resistance to conventional drugs. For this reason, the identification of novel molecular targets and the discovery of new chemotherapeutic agents are urgently required. Metalo- aminopeptidases are promising targets in parasitic infections. They participate in crucial processes for parasite growth and pathogenesis. Objective: In this review, we describe the structural, functional and kinetic properties, and inhibitors, of several parasite metalo-aminopeptidases, for their use as targets in parasitic diseases. Conclusion: Plasmodium falciparum M1 and M17 aminopeptidases are essential enzymes for parasite development, and M18 aminopeptidase could be involved in hemoglobin digestion and erythrocyte invasion and egression. Trypanosoma cruzi, T. brucei and Leishmania major acidic M17 aminopeptidases can play a nutritional role. T. brucei basic M17 aminopeptidase down-regulation delays the cytokinesis. The inhibition of Leishmania basic M17 aminopeptidase could affect parasite viability. L. donovani methionyl aminopeptidase inhibition prevents apoptosis but not the parasite death. Decrease in Acanthamoeba castellanii M17 aminopeptidase activity produces cell wall structural modifications and encystation inhibition. Inhibition of Babesia bovis growth is probably related to the inhibition of the parasite M17 aminopeptidase, probably involved in host hemoglobin degradation. Schistosoma mansoni M17 aminopeptidases inhibition may affect parasite development, since they could participate in hemoglobin degradation, surface membrane remodeling and eggs hatching. Toxoplasma gondii M17 aminopeptidase inhibition could attenuate parasite virulence, since it is apparently involved in the hydrolysis of cathepsin Cs- or proteasome-produced dipeptides and/or cell attachment/invasion processes. These data are relevant to validate these enzymes as targets.
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- 2023
7. Multi-Institution Research and Education Collaboration Identifies New Antimicrobial Compounds
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Amelia A. Fuller, Amy B. Dounay, Mark A. T. Blaskovich, Kristiana Tenorio, Johannes Zuegg, Martin J. O'Donnell, Karl A. Hansford, Yanira Méndez, Sarah Burris-Hiday, Daniel G. Rivera, William L. Scott, J. Geno Samaritoni, Mark E. Cooper, Alysha G. Elliott, Douglas Schirch, and Jacob R Hitchens
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0301 basic medicine ,Knowledge management ,Computer science ,Phenotypic screening ,Microbial Sensitivity Tests ,01 natural sciences ,Biochemistry ,Education ,03 medical and health sciences ,Minimum inhibitory concentration ,Anti-Infective Agents ,Humans ,010405 organic chemistry ,Extramural ,business.industry ,Drug discovery ,Reproducibility of Results ,Articles ,General Medicine ,Antimicrobial ,3. Good health ,0104 chemical sciences ,Antimicrobial drug ,Multiple drug resistance ,Important research ,Interinstitutional Relations ,Organizational Affiliation ,030104 developmental biology ,Molecular Medicine ,business - Abstract
New antibiotics are urgently needed to address increasing rates of multidrug resistant infections. Seventy-six diversely functionalized compounds, comprising five structural scaffolds, were synthesized and tested for their ability to inhibit microbial growth. Twenty-six compounds showed activity in the primary phenotypic screen at the Community for Open Antimicrobial Drug Discovery (CO-ADD). Follow-up testing of active molecules confirmed that two unnatural dipeptides inhibit the growth of Cryptococcus neoformans with a minimum inhibitory concentration (MIC) ≤ 8 μg/mL. Syntheses were carried out by undergraduate students at five schools implementing Distributed Drug Discovery (D3) programs. This report showcases that a collaborative research and educational process is a powerful approach to discover new molecules inhibiting microbial growth. Educational gains for students engaged in this project are highlighted in parallel to the research advances. Aspects of D3 that contribute to its success, including an emphasis on reproducibility of procedures, are discussed to underscore the power of this approach to solve important research problems and to inform other coupled chemical biology research and teaching endeavors.
- Published
- 2020
8. Expanding the Scope of Ugi Multicomponent Bioconjugation to Produce Pneumococcal Multivalent Glycoconjugates as Vaccine Candidates
- Author
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Raine Garrido, Mirelys Saenz, Yanira Méndez, Vicente Verez-Bencomo, Rocmira Perez-Nicado, Daniel G. Rivera, Ana R. Humpierre, Aldrin V. Vasco, Dagmar García-Rivera, Abel Zanuy, Yamilka Soroa-Milán, Bernhard Westermann, and Darielys Santana-Mederos
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Models, Molecular ,Glycoconjugate ,Biomedical Engineering ,Pharmaceutical Science ,Bioengineering ,Chemistry Techniques, Synthetic ,02 engineering and technology ,medicine.disease_cause ,01 natural sciences ,Pneumococcal Infections ,Pneumococcal Vaccines ,Mice ,Antigen ,Streptococcus pneumoniae ,medicine ,Animals ,Humans ,Pharmacology ,chemistry.chemical_classification ,Vaccines, Conjugate ,Bioconjugation ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Toxoid ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,Specific antibody ,Biochemistry ,Carrier protein ,Rabbits ,0210 nano-technology ,Glycoconjugates ,Biotechnology ,Conjugate - Abstract
Conjugate vaccines against encapsulated pathogens like Streptococcus pneumoniae face many challenges, including the existence of multiple serotypes with a diverse global distribution that constantly requires new formulations and higher coverage. Multivalency is usually achieved by combining capsular polysaccharide-protein conjugates from invasive serotypes, and for S. pneumoniae, this has evolved from 7- up to 20-valent vaccines. These glycoconjugate formulations often contain high concentrations of carrier proteins, which may negatively affect glycoconjugate immune response. This work broadens the scope of an efficient multicomponent strategy, leading to multivalent pneumococcal glycoconjugates assembled in a single synthetic operation. The bioconjugation method, based on the Ugi four-component reaction, enables the one-pot incorporation of two different polysaccharide antigens to a tetanus toxoid carrier, thus representing the fastest approach to achieve multivalency. The reported glycoconjugates incorporate three combinations of capsular polysaccharides 1, 6B, 14, and 18C from S. pneumoniae. The glycoconjugates were able to elicit functional specific antibodies against pneumococcal strains comparable to those shown by mixtures of the two monovalent glycoconjugates.
- Published
- 2020
9. Quantitative NMR for the structural analysis of novel bivalent glycoconjugates as vaccine candidates
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Ana R. Humpierre, Abel Zanuy, Mirelys Saenz, Aldrin V. Vasco, Yanira Méndez, Bernhard Westermann, Félix Cardoso, Lauren Quintero, Darielys Santana, Vicente Verez, Yury Valdés, Daniel G. Rivera, and Raine Garrido
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Magnetic Resonance Spectroscopy ,Vaccines, Conjugate ,Polysaccharides ,Clinical Biochemistry ,Drug Discovery ,Polysaccharides, Bacterial ,Pharmaceutical Science ,Glycoconjugates ,Magnetic Resonance Imaging ,Spectroscopy ,Analytical Chemistry - Abstract
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.
- Published
- 2021
10. KBE009: A Bestatin-Like Inhibitor of the Trypanosoma cruzi Acidic M17 Aminopeptidase with In Vitro Anti-Trypanosomal Activity
- Author
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Sabrina Marsiccobetre, Mirtha Elisa Aguado, Katherine Figarella, Yanira Méndez, Irina Arocha, Daniel G. Rivera, Néstor L. Uzcátegui, Jorge González-Bacerio, and Maikel Izquierdo
- Subjects
Chagas disease ,Proteases ,Peptidomimetic ,Trypanosoma cruzi ,In silico ,Science ,protease inhibitors ,bestatin-like peptidomimetics ,chemotherapy ,Article ,General Biochemistry, Genetics and Molecular Biology ,parasitic diseases ,medicine ,Parasite hosting ,Ecology, Evolution, Behavior and Systematics ,biology ,Chemistry ,leucyl-aminopeptidase ,Paleontology ,medicine.disease ,biology.organism_classification ,In vitro ,Biochemistry ,Space and Planetary Science ,Docking (molecular) - Abstract
Chagas disease, caused by the kinetoplastid parasite Trypanosoma cruzi, is a human tropical illness mainly present in Latin America. The therapies available against this disease are far from ideal. Proteases from pathogenic protozoan have been considered as good drug target candidates. T. cruzi acidic M17 leucyl-aminopeptidase (TcLAP) mediates the major parasite’s leucyl-aminopeptidase activity and is expressed in all parasite stages. Here, we report the inhibition of TcLAP (IC50 = 66.0 ± 13.5 µM) by the bestatin-like peptidomimetic KBE009. This molecule also inhibited the proliferation of T. cruzi epimastigotes in vitro (EC50 = 28.1 ± 1.9 µM) and showed selectivity for the parasite over human dermal fibroblasts (selectivity index: 4.9). Further insight into the specific effect of KBE009 on T. cruzi was provided by docking simulation using the crystal structure of TcLAP and a modeled human orthologous, hLAP3. The TcLAP-KBE009 complex is more stable than its hLAP3 counterpart. KBE009 adopted a better geometrical shape to fit into the active site of TcLAP than that of hLAP3. The drug-likeness and lead-likeness in silico parameters of KBE009 are satisfactory. Altogether, our results provide an initial insight into KBE009 as a promising starting point compound for the rational design of drugs through further optimization.
- Published
- 2021
11. SARS-CoV-2 RBD-Tetanus Toxoid Conjugate Vaccine Induces a Strong Neutralizing Immunity in Preclinical Studies
- Author
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Enrique Noa, Ubel Ramirez, Tammy Boggiano, Luis Javier González, Gretchen Bergado, Vicente Verez-Bencomo, Laura Rodriguez, Yury Valdés-Balbín, Raine Garrido, Luis Ariel Espinosa, Yanet Climent, Rocmira Perez, Eduardo Ojito, Kalet León Monzón, Jean-Pierre Soubal, Sonsire Fernández, Daniel G. Rivera, Darielys Santana-Mederos, Felix Cardoso, Claudia Acosta, Lauren Quintero, Yanelys Cabrera Infante, Fabrizio Chiodo, Anamary Suarez, Sum Lai Losada, Tays Hernández, Reinaldo Oliva, Franciscary Pi, Manuel G. Ricardo, Belinda Sánchez Ramírez, Dagmar García-Rivera, Annet Valdes, Mario Landys, Cheng Fang, Yanira Méndez, Juliet Enriquez, Yassel Ramos, Humberto Gonzalez, Guang-Wu Chen, Ernesto Relova-Hernández, Tania Carmenate, Françoise Paquet, Gertrudis Rojas, Mildrey Farinas, Instituto Finlay de Vacunas - Finlay Institute for Vaccines [Havana, Cuba] (IFV), Center of Molecular Immunology, Havana, University of Havana (Universidad de la Habana) (UH), Center for Genetic Engineering and Biotechnology [Cuba] (CIGB), Vrije Universiteit Amsterdam [Amsterdam] (VU), Spanish National Research Council (CSIC), Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), and Sichuan University [Chengdu] (SCU)
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COVID-19 Vaccines ,[SDV]Life Sciences [q-bio] ,Biology ,Biochemistry ,Affinity maturation ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Conjugate vaccine ,Immunity ,medicine ,Tetanus Toxoid ,Animals ,030212 general & internal medicine ,030304 developmental biology ,0303 health sciences ,Mice, Inbred BALB C ,Vaccines, Conjugate ,Tetanus ,SARS-CoV-2 ,Vaccination ,Toxoid ,COVID-19 ,General Medicine ,medicine.disease ,Virology ,Antibodies, Neutralizing ,3. Good health ,Mice, Inbred C57BL ,Immunization ,030220 oncology & carcinogenesis ,Antibody Formation ,biology.protein ,Molecular Medicine ,Antibody - Abstract
Controlling the global COVID-19 pandemic depends, among other measures, on developing preventive vaccines at an unprecedented pace. Vaccines approved for use and those in development intend to use neutralizing antibodies to block viral sites binding to the host’s cellular receptors. Virus infection is mediated by the spike glycoprotein trimer on the virion surface via its receptor binding domain (RBD). Antibody response to this domain is an important outcome of the immunization and correlates well with viral neutralization. Here we show that macromolecular constructs with recombinant RBD conjugated to tetanus toxoid induce a potent immune response in laboratory animals. Some advantages of the immunization with the viral antigen coupled to tetanus toxoid have become evident such as predominant IgG immune response due to affinity maturation and long-term specific B-memory cells. This paper demonstrates that subunit conjugate vaccines can be an alternative for COVID-19, paving the way for other viral conjugate vaccines based on the use of small viral proteins involved in the infection process.
- Published
- 2021
12. Discovery of potent and selective inhibitors of the Escherichia coli M1-aminopeptidase via multicomponent solid-phase synthesis of tetrazole-peptidomimetics
- Author
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Pedro A. Valiente, Maday Alonso del Rivero, Yoanna María Alvarez-Ginarte, Aldrin V. Vasco, Carmen Soto, Yanira Méndez, Tamara Rojas, Bernhard Westermann, Idalia Pérez, German De Armas, Lena de León, Jorge González-Bacerio, Maikel Izquierdo, William L. Scott, Mario E. Valdés-Tresanco, and Daniel G. Rivera
- Subjects
Peptidomimetic ,Tetrazoles ,medicine.disease_cause ,Aminopeptidases ,01 natural sciences ,Aminopeptidase ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Solid-phase synthesis ,Cell Line, Tumor ,Drug Discovery ,Escherichia coli ,medicine ,Animals ,Humans ,Protease Inhibitors ,Tetrazole ,Solid-Phase Synthesis Techniques ,030304 developmental biology ,Pharmacology ,0303 health sciences ,Binding Sites ,010405 organic chemistry ,Drug discovery ,Organic Chemistry ,General Medicine ,Protease inhibitor (biology) ,Anti-Bacterial Agents ,0104 chemical sciences ,Biochemistry ,chemistry ,Peptidomimetics ,Antibacterial activity ,medicine.drug - Abstract
The Escherichia coli neutral M1-aminopeptidase (ePepN) is a novel target identified for the development of antimicrobials. Here we describe a solid-phase multicomponent approach which enabled the discovery of potent ePepN inhibitors. The on-resin protocol, developed in the frame of the Distributed Drug Discovery (D3) program, comprises the implementation of parallel Ugi-azide four-component reactions with resin-bound amino acids, thus leading to the rapid preparation of a focused library of tetrazole-peptidomimetics (TPMs) suitable for biological screening. By dose-response studies, three compounds were identified as potent and selective ePepN inhibitors, as little inhibitory effect was exhibited for the porcine ortholog aminopeptidase. The study allowed for the identification of the key structural features required for a high ePepN inhibitory activity. The most potent and selective inhibitor (TPM 11) showed a non-competitive inhibition profile of ePepN. We predicted that both diastereomers of compound TPM 11 bind to a site distinct from that occupied by the substrate. Theoretical models suggested that TPM 11 has an alternative inhibition mechanism that doesn't involve Zn coordination. On the other hand, the activity landscape analysis provided a rationale for our findings. Of note, compound TMP 2 showed in vitro antibacterial activity against Escherichia coli. Furthermore, none of the three identified inhibitors is a potent haemolytic agent, and only two compounds showed moderate cytotoxic activity toward the murine myeloma P3X63Ag cells. These results point to promising compounds for the future development of rationally designed TPMs as antibacterial agents.
- Published
- 2019
13. Novel Unimolecular Multivalent Glycoconjugates as Antibacterial Vaccine Candidates
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Abel Zanuy Reguera, Mirelys Saenz Pérez, Yanira Méndez Gómez, Bernhard Westermann, Daniel García Rivera, and Ana Rodríguez Humpierre
- Published
- 2020
14. Multicomponent polysaccharide–protein bioconjugation in the development of antibacterial glycoconjugate vaccine candidates
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Dagmar García-Rivera, Abel Zanuy, Darielys Santana, Jessy Pedroso, Ana R. Humpierre, Raine Garrido, Aldrin V. Vasco, Yanira Méndez, Vicente Verez-Bencomo, Laura Rodriguez, Janoi Chang, Daniel G. Rivera, and Yury Valdés
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chemistry.chemical_classification ,Antigenicity ,Bioconjugation ,010405 organic chemistry ,Glycoconjugate ,Biomolecule ,Isocyanide ,General Chemistry ,Conjugated system ,010402 general chemistry ,Polysaccharide ,01 natural sciences ,Combinatorial chemistry ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Antigen - Abstract
A new synthetic strategy for the development of multivalent antibacterial glycoconjugate vaccines is described. The approach comprises the utilization of an isocyanide-based multicomponent process for the conjugation of functionalized capsular polysaccharides of S. pneumoniae and S. Typhi to carrier proteins such as diphtheria and tetanus toxoids. For the first time, oxo- and carboxylic acid-functionalized polysaccharides could be either independently or simultaneously conjugated to immunogenic proteins by means of the Ugi-multicomponent reaction, thus leading to mono- or multivalent unimolecular glycoconjugates as vaccine candidates. Despite the high molecular weight of the two or three reacting biomolecules, the multicomponent bioconjugation proved highly efficient and reproducible. The Ugi-derived glycoconjugates showed notable antigenicity and elicited good titers of functional specific antibodies. To our knowledge, this is the only bioconjugation method that enables the incorporation of two different polysaccharidic antigens to a carrier protein in a single step. Applications in the field of self-adjuvanting, eventually anticancer, multicomponent vaccines are foreseeable.
- Published
- 2018
15. A Multicomponent Stapling Approach to Exocyclic Functionalized Helical Peptides: Adding Lipids, Sugars, PEGs, Labels, and Handles to the Lactam Bridge
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Ludger A. Wessjohann, Yanira Méndez, Daniel G. Rivera, Aldrin V. Vasco, Jochen Balbach, and Andrea Porzel
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Lactams ,Isocyanide ,Carboxylic acid ,Biomedical Engineering ,Chemical biology ,Pharmaceutical Science ,Bioengineering ,Peptide ,02 engineering and technology ,01 natural sciences ,Polyethylene Glycols ,chemistry.chemical_compound ,Side chain ,Pharmacology ,chemistry.chemical_classification ,Bioconjugation ,010405 organic chemistry ,Organic Chemistry ,021001 nanoscience & nanotechnology ,Combinatorial chemistry ,Lipids ,0104 chemical sciences ,chemistry ,Lactam ,Ugi reaction ,0210 nano-technology ,Peptides ,Sugars ,Biotechnology - Abstract
Peptide stapling is traditionally used to lock peptide conformations into α-helical structures using a variety of macrocyclization chemistries. In an endeavor to add a diversity-generating tool to this repertoire, we introduce a multicomponent stapling approach enabling the simultaneous stabilization of helical secondary structures and the exocyclic N-functionalization of the side chain-tethering lactam bridge. This is accomplished by means of a novel solid-phase methodology comprising, for the first time, the on-resin Ugi reaction-based macrocyclization of peptide side chains bearing amino and carboxylic acid groups. The exocyclic diversity elements arise from the isocyanide component used in the Ugi multicomponent stapling protocol, which allows for the incorporation of relevant fragments such as lipids, sugars, polyethylene glycol, fluorescent labels, and reactive handles. We prove the utility of such exocyclic reactive groups in the bioconjugation of a maleimide-armed lactam-bridged peptide to a carrier protein. The on-resin multicomponent stapling proved efficient for the installation of not only one, but also two consecutive lactam bridges having either identical or dissimilar N-functionalities. The easy access to helical peptides with a diverse set of exocyclic functionalities shows prospect for applications in peptide drug discovery and chemical biology.
- Published
- 2018
16. Synthesis of Lactam-Bridged and Lipidated Cyclo-Peptides as Promising Anti-Phytopathogenic Agents
- Author
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Martina Brode, Aldrin V. Vasco, Yanira Méndez, Ludger A. Wessjohann, Daniel G. Rivera, and Oscar Valdés
- Subjects
Circular dichroism ,Antifungal Agents ,Lactams ,Phytophthora infestans ,Isocyanide ,Pharmaceutical Science ,Lipid-anchored protein ,plant pathogens ,010402 general chemistry ,Peptides, Cyclic ,fungicides ,01 natural sciences ,Article ,Analytical Chemistry ,lcsh:QD241-441 ,chemistry.chemical_compound ,lcsh:Organic chemistry ,Drug Discovery ,Amphiphile ,Membrane activity ,Physical and Theoretical Chemistry ,antimycotics ,multicomponent reactions (MCRs) ,peptide cyclization ,010405 organic chemistry ,Organic Chemistry ,Antimicrobial ,lipopeptides ,Combinatorial chemistry ,Anti-Bacterial Agents ,antimicrobial peptides (AMPs) ,0104 chemical sciences ,chemistry ,Chemistry (miscellaneous) ,Lactam ,Molecular Medicine ,Botrytis ,Selectivity - Abstract
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.
- Published
- 2020
17. Multicomponent Reactions in Ligation and Bioconjugation Chemistry
- Author
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Oscar Valdés, L. Reguera, Daniel G. Rivera, Ana R. Humpierre, and Yanira Méndez
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chemistry.chemical_classification ,Natural product ,Bioconjugation ,010405 organic chemistry ,Peptidomimetic ,Biomolecule ,General Medicine ,General Chemistry ,010402 general chemistry ,Special class ,01 natural sciences ,Combinatorial chemistry ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Ligation - Abstract
Multicomponent reactions (MCRs) encompass an exciting class of chemical transformations that have proven success in almost all fields of synthetic organic chemistry. These convergent procedures incorporate three or more reactants into a final product in one pot, thus combining high levels of complexity and diversity generation with low synthetic cost. Striking applications of these processes are found in heterocycle, peptidomimetic, and natural product syntheses. However, their potential in the preparation of large macro- and biomolecular constructs has been realized just recently. This Account describes the most relevant results of our group in the utilization of MCRs for ligation/conjugation of biomolecules along with significant contributions from other laboratories that validate the utility of this special class of bioconjugation process. Thus, MCRs have proven to be efficient in the ligation of lipids to peptides and oligosaccharides as well as the ligation of steroids, carbohydrates, and fluorescent and affinity tags to peptides and proteins. In the field of glycolipids, we highlight the power of isocyanide-based MCRs with the one-pot double lipidation of glycan fragments functionalized as either the carboxylic acid or amine. In peptide chemistry, the versatility of the multicomponent ligation strategy is demonstrated in both solution-phase lipidation protocols and solid-phase procedures enabling the simultaneous lipidation and biotinylation of peptides. In addition, we show that MCRs are powerful methods for synchronized lipidation/labeling and macrocyclization of peptides, thus accomplishing in one step what usually requires long sequences. In the realm of protein bioconjugation, MCRs have also proven to be effective in labeling, site-selective modification, immobilization, and glycoconjugation processes. For example, we illustrate a successful application of multicomponent polysaccharide-protein conjugation with the preparation of multivalent glycoconjugate vaccine candidates by the ligation of two antigenic capsular polysaccharides of a pathogenic bacterium to carrier proteins. By highlighting the ability to join several biomolecules in only one synthetic operation, we hope to encourage the biomolecular chemistry community to apply this powerful chemistry to novel biomedicinal challenges.
- Published
- 2018
18. High-level expression in Escherichia coli, purification and kinetic characterization of Plasmodium falciparum M1-aminopeptidase
- Author
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Jorge González-Bacerio, Yanira Méndez, María A. Chávez, Rafael Fando, Jean-Louis Charli, Katherine Figarella, Joel Osuna, and Amaia Ponce
- Subjects
Codon Adaptation Index ,Proteases ,Plasmodium falciparum ,Biology ,medicine.disease_cause ,Aminopeptidases ,Aminopeptidase ,law.invention ,Affinity chromatography ,Tandem Mass Spectrometry ,law ,Escherichia coli ,medicine ,Codon ,chemistry.chemical_classification ,biology.organism_classification ,Molecular biology ,Recombinant Proteins ,Amino acid ,Kinetics ,chemistry ,Biochemistry ,Proteolysis ,Recombinant DNA ,Biotechnology - Abstract
Plasmodium falciparum neutral metallo-aminopeptidase (PfAM1), a member of the M1 family of metallo proteases, is a promising target for malaria, a devastating human parasitic disease. We report the high-level expression of PfAM1 in Escherichia coli BL21. An optimized gene, with a codon adaptation index and an average G/C content higher than the native gene, was synthesized and cloned in the pTrcHis2B vector. Optimal expression was achieved by induction with 1 mM IPTG at 37 °C for 18 h. This allowed obtaining 100 mg of recombinant PfAM1 (rPfAM1) per L of culture medium; 19% of the E. coli soluble protein mass was from rPFAM1. rPfAM1, fused to an amino-terminal 6×His tag, was purified in a single step by immobilized metal ion affinity chromatography. The protein showed only limited signs of proteolytic degradation, and this step increased purity 27-fold. The kinetic characteristics of rPfAM1, such as a neutral optimal pH, a preference for substrates with basic or hydrophobic amino acids at the P1 position, an inhibition profile typical of metallo-aminopeptidases, and inhibition from Zn2+ excess, were similar to those of the native PfAM1. We have thus optimized an expression system that should be useful for identifying new PfAM1 inhibitors.
- Published
- 2014
19. KBE009: An antimalarial bestatin-like inhibitor of the Plasmodium falciparum M1 aminopeptidase discovered in an Ugi multicomponent reaction-derived peptidomimetic library
- Author
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Juliana C. Ferreira, Maday Alonso del Rivero, Ernesto Moreno, Yanira Méndez, Alexandre Budu, Isabelle Florent, Adriana K. Carmona, Daniel G. Rivera, Jorge González-Bacerio, Isel Pascual, Sarah El Chamy Maluf, Pollyana M.S. Melo, Marcos L. Gazarini, Departamento de Biofisica, Universidade Federal de Sao Paulo, Molécules de Communication et Adaptation des Micro-organismes (MCAM), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Universidad Nacional de Colombia Sede Medellín, Instituto de Biociencias, Departamento de Zoologia, Universidade de São Paulo (USP), and Universidade de São Paulo = University of São Paulo (USP)
- Subjects
0301 basic medicine ,Erythrocytes ,Peptidomimetic ,Cell Survival ,030106 microbiology ,Clinical Biochemistry ,Plasmodium falciparum ,Protozoan Proteins ,Pharmaceutical Science ,CD13 Antigens ,Biochemistry ,Aminopeptidase ,03 medical and health sciences ,Antimalarials ,Structure-Activity Relationship ,Leucine ,Catalytic Domain ,Drug Discovery ,Human Umbilical Vein Endothelial Cells ,Humans ,[CHIM]Chemical Sciences ,Molecular Biology ,IC50 ,ComputingMilieux_MISCELLANEOUS ,chemistry.chemical_classification ,Binding Sites ,biology ,Chemistry ,Organic Chemistry ,Active site ,Dipeptides ,biology.organism_classification ,In vitro ,Recombinant Proteins ,3. Good health ,Molecular Docking Simulation ,030104 developmental biology ,Enzyme ,Docking (molecular) ,biology.protein ,Molecular Medicine ,Peptidomimetics - Abstract
Malaria is a global human parasitic disease mainly caused by the protozoon Plasmodium falciparum. Increased parasite resistance to current drugs determines the relevance of finding new treatments against new targets. A novel target is the M1 alanyl-aminopeptidase from P. falciparum (PfA-M1), which is essential for parasite development in human erythrocytes and is inhibited by the pseudo-peptide bestatin. In this work, we used a combinatorial multicomponent approach to produce a library of peptidomimetics and screened it for the inhibition of recombinant PfA-M1 (rPfA-M1) and the in vitro growth of P. falciparum erythrocytic stages (3D7 and FcB1 strains). Dose-response studies with selected compounds allowed identifying the bestatin-based peptidomimetic KBE009 as a submicromolar rPfA-M1 inhibitor (Ki=0.4μM) and an in vitro antimalarial compound as potent as bestatin (IC50=18μM; without promoting erythrocyte lysis). At therapeutic-relevant concentrations, KBE009 is selective for rPfA-M1 over porcine APN (a model of these enzymes from mammals), and is not cytotoxic against HUVEC cells. Docking simulations indicate that this compound binds PfA-M1 without Zn2+ coordination, establishing mainly hydrophobic interactions and showing a remarkable shape complementarity with the active site of the enzyme. Moreover, KBE009 inhibits the M1-type aminopeptidase activity (Ala-7-amido-4-methylcoumarin substrate) in isolated live parasites with a potency similar to that of the antimalarial activity (IC50=82μM), strongly suggesting that the antimalarial effect is directly related to the inhibition of the endogenous PfA-M1. These results support the value of this multicomponent strategy to identify PfA-M1 inhibitors, and make KBE009 a promising hit for drug development against malaria.
- Published
- 2017
20. Repercusión social de la halitosis.
- Author
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Hechavarría Martínez, Bárbara Olaydis, Jiménez, Ruth Ramón, and Nápoles, Yanira Méndez
- Abstract
Copyright of MEDISAN is the property of Centro Provincial de Informacion en Ciencias Medicas de Santiago de Cuba and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2014
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