Síntesis y cribado de péptidos modificados derivados de lactoferricina bovina como fármacos citotóxicos contra líneas de cáncer de colon

Ilustraciones a color, diagramas

Autores:: Cárdenas Martínez, Karen Johanna

Tipo de recurso:: Doctoral thesis

Fecha de publicación:: 2024

Institución:: Universidad Nacional de Colombia

Repositorio:: Universidad Nacional de Colombia

Idioma:: spa

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network_acronym_str	UNACIONAL2
network_name_str	Universidad Nacional de Colombia
repository_id_str
dc.title.spa.fl_str_mv	Síntesis y cribado de péptidos modificados derivados de lactoferricina bovina como fármacos citotóxicos contra líneas de cáncer de colon
dc.title.translated.eng.fl_str_mv	Synthesis and screening of modified peptides derived from bovine lactoferricin as cytotoxic drugs against colon cancer cell lines
title	Síntesis y cribado de péptidos modificados derivados de lactoferricina bovina como fármacos citotóxicos contra líneas de cáncer de colon
spellingShingle	Síntesis y cribado de péptidos modificados derivados de lactoferricina bovina como fármacos citotóxicos contra líneas de cáncer de colon 540- Química y Ciencias Afines 570 - Biología::572 - Bioquímica Lactoferrina Peptidos Cancer Peptidos Lactoferricina bovina péptido hit péptido optimizado cáncer de colon
title_short	Síntesis y cribado de péptidos modificados derivados de lactoferricina bovina como fármacos citotóxicos contra líneas de cáncer de colon
title_full	Síntesis y cribado de péptidos modificados derivados de lactoferricina bovina como fármacos citotóxicos contra líneas de cáncer de colon
title_fullStr	Síntesis y cribado de péptidos modificados derivados de lactoferricina bovina como fármacos citotóxicos contra líneas de cáncer de colon
title_full_unstemmed	Síntesis y cribado de péptidos modificados derivados de lactoferricina bovina como fármacos citotóxicos contra líneas de cáncer de colon
title_sort	Síntesis y cribado de péptidos modificados derivados de lactoferricina bovina como fármacos citotóxicos contra líneas de cáncer de colon
dc.creator.fl_str_mv	Cárdenas Martínez, Karen Johanna
dc.contributor.advisor.none.fl_str_mv	García Castañeda, Javier Eduardo
dc.contributor.author.none.fl_str_mv	Cárdenas Martínez, Karen Johanna
dc.contributor.orcid.spa.fl_str_mv	Cárdenas Martínez, Karen Johanna [0000-0002-7266-8769]
dc.subject.ddc.spa.fl_str_mv	540- Química y Ciencias Afines 570 - Biología::572 - Bioquímica
topic	540- Química y Ciencias Afines 570 - Biología::572 - Bioquímica Lactoferrina Peptidos Cancer Peptidos Lactoferricina bovina péptido hit péptido optimizado cáncer de colon
dc.subject.other.spa.fl_str_mv	Lactoferrina
dc.subject.lemb.spa.fl_str_mv	Peptidos Cancer
dc.subject.proposal.spa.fl_str_mv	Peptidos Lactoferricina bovina péptido hit péptido optimizado cáncer de colon
description	Ilustraciones a color, diagramas
publishDate	2024
dc.date.accessioned.none.fl_str_mv	2024-07-18T16:32:38Z
dc.date.available.none.fl_str_mv	2024-07-18T16:32:38Z
dc.date.issued.none.fl_str_mv	2024-07
dc.type.spa.fl_str_mv	Trabajo de grado - Doctorado
dc.type.driver.spa.fl_str_mv	info:eu-repo/semantics/doctoralThesis
dc.type.version.spa.fl_str_mv	info:eu-repo/semantics/acceptedVersion
dc.type.coar.spa.fl_str_mv	http://purl.org/coar/resource_type/c_db06
dc.type.content.spa.fl_str_mv	Text
dc.type.redcol.spa.fl_str_mv	http://purl.org/redcol/resource_type/TD
format	http://purl.org/coar/resource_type/c_db06
status_str	acceptedVersion
dc.identifier.uri.none.fl_str_mv	https://repositorio.unal.edu.co/handle/unal/86567
dc.identifier.instname.spa.fl_str_mv	Universidad Nacional de Colombia
dc.identifier.reponame.spa.fl_str_mv	Repositorio Institucional Universidad Nacional de Colombia
dc.identifier.repourl.spa.fl_str_mv	https://repositorio.unal.edu.co/
url	https://repositorio.unal.edu.co/handle/unal/86567 https://repositorio.unal.edu.co/
identifier_str_mv	Universidad Nacional de Colombia Repositorio Institucional Universidad Nacional de Colombia
dc.language.iso.spa.fl_str_mv	spa
language	spa
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spelling	Atribución-NoComercial-SinDerivadas 4.0 Internacionalinfo:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2García Castañeda, Javier Eduardod233ac45968135ded4a8bcbe0460b111Cárdenas Martínez, Karen Johanna0595f55667880f609d3a8ee840186f50Cárdenas Martínez, Karen Johanna [0000-0002-7266-8769]2024-07-18T16:32:38Z2024-07-18T16:32:38Z2024-07https://repositorio.unal.edu.co/handle/unal/86567Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/Ilustraciones a color, diagramasResearch on anticancer peptide drugs has gained interest due to their potency and selectivity. Bovine Lactoferricin (LfcinB) and derived peptides, as used in this study, have shown cytotoxic activity against breast cancer. Therefore, their effect on colon cancer was evaluated, specifically on Caco-2 and HT-29 cell lines, with the latter being more resistant. Two hit peptides, LfcinB (21-25)Pal and 26[F] LfcinB (20-30)2, were identified. Libraries of monomeric and dimeric peptides were constructed from these, resulting in 34 molecules. Their cytotoxic effect was assessed on colon cancer cell lines. This process allowed the identification of key amino acids in the sequence necessary for cytotoxic activity and modifications of interest to enhance it. Fifteen molecules exhibited inhibitory concentrations (IC50) below 200 μg/mL against colon cancer cell lines, with eight considered optimized peptides due to improved activity and selectivity. They remained active in colon cancer cell lines from 2 to 72 hours, showing cytotoxicity in prostate, cervical, and breast cancer lines. Optimized peptides, particularly 3, 19, and LfcinB (21-25)Pal, induced cell death in HT-29 cells primarily through the apoptotic pathway, causing mitochondrial membrane depolarization, caspase overexpression, and morphological changes such as rounding and cell contraction. The toxicity of optimized peptides 3, 19, LfcinB (21-25)Pal, and LfcinB (21-25)Pal2 was evaluated in Galleria mellonella, finding lethal doses (LD50) >100mg/kg. Moreover, peptide 19 toxicity was assessed in CD1 mice through the Irwin test, revealing central nervous system effects with LD50 between 70mg/kg and 140mg/kg. Lastly, the zebrafish model determined the CL50 of this optimized peptide to be between 20-25 μg/mL. It was also found that this optimized peptide exhibited lower in vivo toxicity than the sequence-derived peptide (hit). Based on the results, eight optimized peptides were identified, with peptides 3, 19, and LfcinB (21-25)Pal standing out as candidates for further studies in developing treatments for colon cancer.La investigación en fármacos de origen peptídico anticancerígenos ha ganado interés debido a su potencia y selectividad. La Lactoferricina Bovina (LfcinB) y péptidos derivados, como los utilizados en el presente estudio han mostrado actividad citotóxica frente a cáncer de mama, por lo que se evaluó su efecto sobre cáncer de colon (líneas celulares Caco-2 y HT-29, siendo esta última la más resistente). Se identificaron dos péptidos hit, LfcinB (21-25)Pal y 26[F] LfcinB (20-30)2, a partir de los cuales se construyeron librerías de péptidos monoméricos y diméricos para la obtención de 34 moléculas, cuyo efecto citotóxico se evaluó en líneas celulares de cáncer de colon. Este proceso permitió la identificación de aminoácidos clave de la secuencia que son o no necesarios para la actividad citotóxica y modificaciones de interés para mejorar la actividad. Quince moléculas mostraron concentraciones inhibitorias (IC50) menores de 200 μg/mL frente a las líneas celulares de cáncer de colon, de los cuales ocho fueron considerados como péptidos optimizados por su actividad y selectividad mejorada. Estos fueron activos en líneas celulares de cáncer de colon desde las 2 hasta las 72 horas de tratamiento, algunas también demostraron citotoxicidad en líneas de cáncer de próstata, cuello uterino y mama. Los péptidos optimizados con los mejores resultados 3, 19 y el LfcinB (21-25)Pal indujeron muerte celular en células HT-29 por la vía apoptótica principalmente, causando despolarización de la membrana mitocondrial, sobreexpresión de caspasas y cambios morfológicos como redondeamiento y contracción celular. La toxicidad de los péptidos optimizados 3, 19, LfcinB (21-25)Pal y el LfcinB (21-25)Pal2 fue evaluada en Galleria mellonella, encontrando dosis letales (DL50) >100mg/kg. Por otro lado, la toxicidad del péptido 19 fue evaluada en ratones CD1 mediante la prueba de Irwin, evidenciando que el péptido indujo efectos en el sistema nervioso central y la DL50 está entre 70mg/kg y 140mg/kg. Por último, en el modelo de pez cebra se determinó que la CL50 de este péptido está entre 20-25 μg/mL. Así mismo, se evidenció que este péptido optimizado presentó menor toxicidad in vivo que el péptido del que se derivó su secuencia (péptido hit). A partir de los resultados obtenidos se identificaron ocho péptidos optimizados, de los cuales se destacan los péptidos 3, 19 y LfcinB (21-25)Pal como candidatos para continuar en estudios para el desarrollo de tratamientos contra el cáncer de colon. 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Síntesis y cribado de péptidos modificados derivados de lactoferricina bovina como fármacos citotóxicos contra líneas de cáncer de colon

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