Efecto antiviral in vitro e in silico de extractos derivados de café en un modelo de infección por el virus del dengue

La enfermedad del dengue representa un problema grave en la salud pública a nivel mundial, debido a la amplia distribución del vector, estrategia de control ineficientes, dificultad en el acceso y eficacia de vacunas y ausencia de antivirales aprobados. Los extractos naturales, especialmente aquello...

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Autores:: Gaitán Veloza, Gustavo Andrés

Tipo de recurso:

Fecha de publicación:: 2025

Institución:: Universidad de Antioquia

Repositorio:: Repositorio UdeA

Idioma:: spa

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network_acronym_str	UDEA2
network_name_str	Repositorio UdeA
repository_id_str
dc.title.spa.fl_str_mv	Efecto antiviral in vitro e in silico de extractos derivados de café en un modelo de infección por el virus del dengue
title	Efecto antiviral in vitro e in silico de extractos derivados de café en un modelo de infección por el virus del dengue
spellingShingle	Efecto antiviral in vitro e in silico de extractos derivados de café en un modelo de infección por el virus del dengue Residuos de café Coffee waste Virus del dengue Dengue virus Antivirales Antiviral agents Células U937 U937 Cells Técnicas in vitro In vitro techniques Simulación por computador Computer simulation Coffea arabica Serotipo Serotypes http://aims.fao.org/aos/agrovoc/c_1721 http://aims.fao.org/aos/agrovoc/c_32699 http://id.loc.gov/authorities/subjects/sh85027725 https://id.nlm.nih.gov/mesh/D003716 https://id.nlm.nih.gov/mesh/D000998 https://id.nlm.nih.gov/mesh/D020298 https://id.nlm.nih.gov/mesh/D066298 https://id.nlm.nih.gov/mesh/D003198 ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades ODS 9: Industria, innovación e infraestructura. Construir infraestructuras resilientes, promover la industrialización inclusiva y sostenible y fomentar la innovación ODS 12: Producción y consumo responsables. Garantizar modalidades de consumo y producción sostenibles
title_short	Efecto antiviral in vitro e in silico de extractos derivados de café en un modelo de infección por el virus del dengue
title_full	Efecto antiviral in vitro e in silico de extractos derivados de café en un modelo de infección por el virus del dengue
title_fullStr	Efecto antiviral in vitro e in silico de extractos derivados de café en un modelo de infección por el virus del dengue
title_full_unstemmed	Efecto antiviral in vitro e in silico de extractos derivados de café en un modelo de infección por el virus del dengue
title_sort	Efecto antiviral in vitro e in silico de extractos derivados de café en un modelo de infección por el virus del dengue
dc.creator.fl_str_mv	Gaitán Veloza, Gustavo Andrés
dc.contributor.advisor.none.fl_str_mv	Martínez Gutiérrez, Marlén Loaiza Cano, Vanessa
dc.contributor.author.none.fl_str_mv	Gaitán Veloza, Gustavo Andrés
dc.contributor.referee.none.fl_str_mv	Roja Hoyos, Luisa Fernanda
dc.contributor.researchgroup.none.fl_str_mv	Grupo de Investigación en Ciencias Agrarias -GRICA- Grupo de Investigación en Microbiología Básica y Aplicada-Microba
dc.contributor.jury.none.fl_str_mv	Delgado Tiria, Félix Giovanni Betancur Galvis, Liliana Amparo
dc.subject.lcsh.none.fl_str_mv	Residuos de café Coffee waste
topic	Residuos de café Coffee waste Virus del dengue Dengue virus Antivirales Antiviral agents Células U937 U937 Cells Técnicas in vitro In vitro techniques Simulación por computador Computer simulation Coffea arabica Serotipo Serotypes http://aims.fao.org/aos/agrovoc/c_1721 http://aims.fao.org/aos/agrovoc/c_32699 http://id.loc.gov/authorities/subjects/sh85027725 https://id.nlm.nih.gov/mesh/D003716 https://id.nlm.nih.gov/mesh/D000998 https://id.nlm.nih.gov/mesh/D020298 https://id.nlm.nih.gov/mesh/D066298 https://id.nlm.nih.gov/mesh/D003198 ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades ODS 9: Industria, innovación e infraestructura. Construir infraestructuras resilientes, promover la industrialización inclusiva y sostenible y fomentar la innovación ODS 12: Producción y consumo responsables. Garantizar modalidades de consumo y producción sostenibles
dc.subject.decs.none.fl_str_mv	Virus del dengue Dengue virus Antivirales Antiviral agents Células U937 U937 Cells Técnicas in vitro In vitro techniques Simulación por computador Computer simulation
dc.subject.agrovoc.none.fl_str_mv	Coffea arabica Serotipo Serotypes
dc.subject.agrovocuri.none.fl_str_mv	http://aims.fao.org/aos/agrovoc/c_1721 http://aims.fao.org/aos/agrovoc/c_32699
dc.subject.lcshuri.none.fl_str_mv	http://id.loc.gov/authorities/subjects/sh85027725
dc.subject.meshuri.none.fl_str_mv	https://id.nlm.nih.gov/mesh/D003716 https://id.nlm.nih.gov/mesh/D000998 https://id.nlm.nih.gov/mesh/D020298 https://id.nlm.nih.gov/mesh/D066298 https://id.nlm.nih.gov/mesh/D003198
dc.subject.ods.none.fl_str_mv	ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades ODS 9: Industria, innovación e infraestructura. Construir infraestructuras resilientes, promover la industrialización inclusiva y sostenible y fomentar la innovación ODS 12: Producción y consumo responsables. Garantizar modalidades de consumo y producción sostenibles
description	La enfermedad del dengue representa un problema grave en la salud pública a nivel mundial, debido a la amplia distribución del vector, estrategia de control ineficientes, dificultad en el acceso y eficacia de vacunas y ausencia de antivirales aprobados. Los extractos naturales, especialmente aquellos provenientes de plantas, han sido de interés en el desarrollo de compuestos antivirales, por su prometedor potencial terapéutico. Actualmente, gracias al desarrollo de negocios sostenibles y la valorización de residuos agroindustriales, los residuos generados durante el beneficio del café, que generan un impacto ambiental desfavorable, podrían convertirse en extractos como fuente potencial de metabolitos secundarios clave como los ácidos clorogénicos, los cuales han mostrado actividad antioxidante y capacidad antiviral. Por esto, se evaluó el efecto antiviral in vitro e in silico de extractos hidroalcohólicos de cáscara de café de Coffea arabica contra cuatro serotipos del DENV. Se evaluó la viabilidad de células U937 (monocitos humanos derivados de linfoma) tratadas a concentraciones seriadas de 0.031 a 1.0% del extracto, para seleccionar la concentración de uso. Se evaluó la actividad antiviral por estrategia combinada, y el posible mecanismo por estrategias individuales pre, trans y postratamiento en células U937 infectadas con una cepa de cada serotipo de DENV (MOI: 0.5), tratándolas con una concentración no citotóxica del extracto. Se cuantificaron las UFP/mL mediante ensayo de plaqueo, el número de copias genómicas/mL por qPCR y la proteína viral por Cell-ELISA. Se identificaron los metabolitos del extracto por UHPLC-MS/Orbitrap y se evaluaron in silico por acoplamiento molecular con proteínas virales de DENV. Se observó que la viabilidad celular fue superior al 80% en todas las concentraciones del extracto evaluadas durante 72h de tratamiento y superior al 90% a 0.063%, concentración seleccionada para las evaluaciones antivirales; la estrategia combinada resultó en una inhibición de las partículas virales infecciosas de los cuatro serotipos, con disminuciones del 85.3% (DENV-1), 86.7% (DENV-2), 95.1% (DENV-3) y 39.6% (DENV-4); las estrategias individuales pre, trans y postratamiento, evidenciaron un efecto virucida contra DENV-2 con un 74,2% de inhibición, y actividad inhibitoria en el postratamiento para DENV-1, DENV-2 y DENV-3 del 42.4%, 31.1% y 38.3%, respectivamente. Adicionalmente, no se observó inhibición de copias genómicas/mL en los diferentes serotipos a excepción de DENV-3 con una reducción del 51.6%, y tampoco se redujo la producción de proteínas virales; lo que sugiere una interferencia en fases tardías del ciclo replicativo como ensamblaje, maduración o liberación viral en los serotipos 1 y 2. In silico, el ácido dicafeoilquínico mostró la mejor afinidad con las proteínas E y NS2B-NS3 de DENV-2, mientras que el ácido clorogénico destacó en NS5 de DENV-3. Los resultados obtenidos evidencian actividad antiviral del extracto de cáscara de café frente a los cuatro serotipos, con un posible mecanismo antiviral dependiente del serotipo, destacando el potencial del extracto de cáscara de café como fuente de compuestos bioactivos para el desarrollo de terapias alternativas contra la infección por DENV, no solo contribuyendo a proponer soluciones para el problema de salud pública, sino valorización un desecho de la cadena productiva del café.
publishDate	2025
dc.date.accessioned.none.fl_str_mv	2025-10-23T15:46:01Z
dc.date.issued.none.fl_str_mv	2025
dc.date.available.none.fl_str_mv	2027-10-23
dc.type.none.fl_str_mv	Trabajo de grado - Maestría
dc.type.redcol.none.fl_str_mv	http://purl.org/redcol/resource_type/TM
dc.type.content.none.fl_str_mv	Text
dc.type.coarversion.none.fl_str_mv	http://purl.org/coar/version/c_b1a7d7d4d402bcce
dc.type.driver.none.fl_str_mv	info:eu-repo/semantics/masterThesis
dc.type.version.none.fl_str_mv	info:eu-repo/semantics/draft
status_str	draft
dc.identifier.citation.none.fl_str_mv	Gaitán Veloza, G. A. (2025). Efecto antiviral in vitro e in silico de extractos derivados de café en un modelo de infección por el virus del dengue [Tesis de maestría]. Universidad de Antioquia, Medellín, Colombia.
dc.identifier.uri.none.fl_str_mv	https://hdl.handle.net/10495/47918
identifier_str_mv	Gaitán Veloza, G. A. (2025). Efecto antiviral in vitro e in silico de extractos derivados de café en un modelo de infección por el virus del dengue [Tesis de maestría]. Universidad de Antioquia, Medellín, Colombia.
url	https://hdl.handle.net/10495/47918
dc.language.iso.none.fl_str_mv	spa
language	spa
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spelling	Martínez Gutiérrez, MarlénLoaiza Cano, VanessaGaitán Veloza, Gustavo AndrésRoja Hoyos, Luisa FernandaGrupo de Investigación en Ciencias Agrarias -GRICA-Grupo de Investigación en Microbiología Básica y Aplicada-MicrobaDelgado Tiria, Félix GiovanniBetancur Galvis, Liliana Amparo2025-10-23T15:46:01Z2027-10-232025Gaitán Veloza, G. A. (2025). Efecto antiviral in vitro e in silico de extractos derivados de café en un modelo de infección por el virus del dengue [Tesis de maestría]. Universidad de Antioquia, Medellín, Colombia.https://hdl.handle.net/10495/47918La enfermedad del dengue representa un problema grave en la salud pública a nivel mundial, debido a la amplia distribución del vector, estrategia de control ineficientes, dificultad en el acceso y eficacia de vacunas y ausencia de antivirales aprobados. Los extractos naturales, especialmente aquellos provenientes de plantas, han sido de interés en el desarrollo de compuestos antivirales, por su prometedor potencial terapéutico. Actualmente, gracias al desarrollo de negocios sostenibles y la valorización de residuos agroindustriales, los residuos generados durante el beneficio del café, que generan un impacto ambiental desfavorable, podrían convertirse en extractos como fuente potencial de metabolitos secundarios clave como los ácidos clorogénicos, los cuales han mostrado actividad antioxidante y capacidad antiviral. Por esto, se evaluó el efecto antiviral in vitro e in silico de extractos hidroalcohólicos de cáscara de café de Coffea arabica contra cuatro serotipos del DENV. Se evaluó la viabilidad de células U937 (monocitos humanos derivados de linfoma) tratadas a concentraciones seriadas de 0.031 a 1.0% del extracto, para seleccionar la concentración de uso. Se evaluó la actividad antiviral por estrategia combinada, y el posible mecanismo por estrategias individuales pre, trans y postratamiento en células U937 infectadas con una cepa de cada serotipo de DENV (MOI: 0.5), tratándolas con una concentración no citotóxica del extracto. Se cuantificaron las UFP/mL mediante ensayo de plaqueo, el número de copias genómicas/mL por qPCR y la proteína viral por Cell-ELISA. Se identificaron los metabolitos del extracto por UHPLC-MS/Orbitrap y se evaluaron in silico por acoplamiento molecular con proteínas virales de DENV. Se observó que la viabilidad celular fue superior al 80% en todas las concentraciones del extracto evaluadas durante 72h de tratamiento y superior al 90% a 0.063%, concentración seleccionada para las evaluaciones antivirales; la estrategia combinada resultó en una inhibición de las partículas virales infecciosas de los cuatro serotipos, con disminuciones del 85.3% (DENV-1), 86.7% (DENV-2), 95.1% (DENV-3) y 39.6% (DENV-4); las estrategias individuales pre, trans y postratamiento, evidenciaron un efecto virucida contra DENV-2 con un 74,2% de inhibición, y actividad inhibitoria en el postratamiento para DENV-1, DENV-2 y DENV-3 del 42.4%, 31.1% y 38.3%, respectivamente. Adicionalmente, no se observó inhibición de copias genómicas/mL en los diferentes serotipos a excepción de DENV-3 con una reducción del 51.6%, y tampoco se redujo la producción de proteínas virales; lo que sugiere una interferencia en fases tardías del ciclo replicativo como ensamblaje, maduración o liberación viral en los serotipos 1 y 2. In silico, el ácido dicafeoilquínico mostró la mejor afinidad con las proteínas E y NS2B-NS3 de DENV-2, mientras que el ácido clorogénico destacó en NS5 de DENV-3. Los resultados obtenidos evidencian actividad antiviral del extracto de cáscara de café frente a los cuatro serotipos, con un posible mecanismo antiviral dependiente del serotipo, destacando el potencial del extracto de cáscara de café como fuente de compuestos bioactivos para el desarrollo de terapias alternativas contra la infección por DENV, no solo contribuyendo a proponer soluciones para el problema de salud pública, sino valorización un desecho de la cadena productiva del café.Dengue fever is a major global public health problem due to the widespread distribution of its vector, inefficient control strategies, limited vaccine access, and the lack of effective antiviral treatments. Natural extracts, particularly those derived from plants, have gained interest in antiviral drug development due to their promising therapeutic potential. Coffee by-products, which normally generate a negative environmental impact, contain secondary metabolites with bioactive and antiviral properties. For this reason, the in vitro and in silico antiviral effect of Coffea arabica husk extracts against all four DENV serotypes was evaluated. The viability of U937 (human monocytes derived from lymphoma) cells treated with serial extract concentrations %v/v (1.0 to 0.031%) was assessed. Antiviral strategies combined, pre, trans, and post-treatment were performed on U937 cells infected with each DENV serotype (MOI: 0.5) using a non-cytotoxic extract concentration (0.063%). Viral particles (PFU/mL) were quantified via plaque assays, while genomic copies and viral proteins were measured via qPCR and Cell-ELISA, respectively. Results showed cell viability remained above 80% at all extract concentrations after 72 hours of treatment. The combined strategy significantly inhibited infectious viral particles across all serotypes, with reductions of 85.3% (DENV-1), 86.7% (DENV-2), 95.1% (DENV-3), and 39.6% (DENV-4). Individual strategies revealed a virucidal effect against DENV-2 (74.2% inhibition) and post-treatment activity against DENV-1 (42.4%), DENV-2 (31.1%), and DENV-3 (38.3%). Additionally, no significant reduction in genomic copies was observed except for DENV-3 (51.6% decrease), demonstrating inhibition in genomic replication in that serotype, no reduction in viral protein production was observed in any of the four serotypes; suggesting interference in late phases of the replicative cycle such as viral assembly, maturation or release in serotypes 1 and 2. In silico, dicaffeoylquinic acid showed the best affinity with DENV-2 E and NS2B-NS3 proteins, while chlorogenic acid was preferred by DENV-3 NS5. In conclusion, the coffee husk extract exhibits serotype-dependent antiviral activity, highlighting its potential as a source of bioactive compounds for alternative dengue therapies. This research not only contributes to public health but also adds value to a waste product from the coffee production chain.1 MARCO TEÓRICO 1.1 VIRUS DEL DENGUE (DENV) 1.1.1 Epidemiología 1.1.2 Agente etiológico 1.1.3 Ciclo replicativo 1.1.4 Patogénesis 1.1.5 Manifestaciones clínicas 1.1.6 Estrategias de control 1.2 ANTIVIRALES 1.2.1 Mecanismos de acción 1.2.2 Búsqueda de antivirales 1.2.3 Plantas como fuente para el desarrollo de antivirales 1.3 PLANTA DE INTERÉS EN ESTE ESTUDIO Coffea arabica L. 1.3.1 Taxonomía 1.3.2 Importancia socioeconómica del café 1.3.3 Proceso de beneficiado húmedo del café 1.3.4 Potencial bioactivo 2 ANTECEDENTES 2.1 Actividad antiviral de extractos derivados del café 2.2 Extractos de origen natural con potencial antiviral contra el DENV 2.3 Antecedentes del grupo de investigación 3 PLANTEAMIENTO DEL PROBLEMA 4 PREGUNTA DE INVESTIGACIÓN 5 OBJETIVOS 5.1 Objetivo General 5.2 Objetivos específicos 6 METODOLOGÍA 6.1 Extracto de cáscara de café 6.2 Células 6.3 Cepas virales 6.3.1 Producciones virales 6.4 Ensayo de citotoxicidad por MTT 6.5 Estrategias para las evaluaciones antivirales in vitro 6.5.1 Estrategia antiviral combinada 6.5.2 Estrategia Pre-tratamiento 6.5.3 Estrategia Trans-tratamiento 6.5.4 Estrategia Post-tratamiento 6.6 Cuantificación viral 6.6.1 Cuantificación de partículas virales infecciosas: Ensayos de plaqueo 6.6.2 Cuantificación de genoma viral: Extracción de ARN viral y PCR en tiempo real 6.6.3 Cuantificación de las proteínas virales: Cell-ELISA 6.6.4 Análisis estadístico 6.7 Evaluación in silico de la afinidad de los compuestos presentes en el extracto de cáscara de café con proteínas virales aplicando acoplamiento molecular 7 RESULTADOS 7.1 El extracto de cáscara de café no afecta la viabilidad de las células U937 7.2 El extracto de cáscara de café presenta actividad antiviral contra los cuatro serotipos del DENV en una estrategia combinada 7.3 El extracto de cáscara de café actúa en etapas tardías del ciclo viral de DENV-1 7.4 El extracto de cáscara de café posee efecto virucida y actúa en etapas tardías del ciclo viral de DENV-2 7.5 El extracto de cáscara de café actúa en etapas tardías del ciclo viral de DENV-3 7.6 El extracto de cáscara de café no actúa en estrategias individuales pre, trans y post tratamiento contra DENV-4 7.7 Cuantificación de copias genómicas de monocapas de la estrategia antiviral Post tratamiento de DENV-1, DENV-2, DENV-3 y DENV-4 7.8 Cuantificación de proteínas de monocapas de la estrategia antiviral Post-tratamiento de DENV-1, DENV-2, DENV-3 y DENV-4 7.9 Los compuestos presentes en el extracto de cáscara de café presentan interacciones favorables con proteínas del DENV 8 DISCUSIÓN 9 CONCLUSIÓN 10 PERSPECTIVAS 11 BIBLIOGRAFÍAAntiviralesCOL0009556COL0126131MaestríaMagíster en Microbiología64 páginasapplication/pdfspaUniversidad de AntioquiaMaestría en MicrobiologíaMedellín, ColombiaEscuela de MicrobiologíaCampus Medellín - Ciudad Universitariahttp://creativecommons.org/licenses/by-nc-sa/4.0/info:eu-repo/semantics/openAccessAttribution-NonCommercial-ShareAlike 4.0 Internationalhttp://purl.org/coar/access_right/c_abf2Residuos de caféCoffee wasteVirus del dengueDengue virusAntiviralesAntiviral agentsCélulas U937U937 CellsTécnicas in vitroIn vitro techniquesSimulación por computadorComputer simulationCoffea arabicaSerotipoSerotypeshttp://aims.fao.org/aos/agrovoc/c_1721http://aims.fao.org/aos/agrovoc/c_32699http://id.loc.gov/authorities/subjects/sh85027725https://id.nlm.nih.gov/mesh/D003716https://id.nlm.nih.gov/mesh/D000998https://id.nlm.nih.gov/mesh/D020298https://id.nlm.nih.gov/mesh/D066298https://id.nlm.nih.gov/mesh/D003198ODS 3: Salud y bienestar. 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

Efecto antiviral in vitro e in silico de extractos derivados de café en un modelo de infección por el virus del dengue

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