Diseño de agentes de transfección de ácidos nucleicos basados en péptidos autoensamblados
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Fecha
2024
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Idioma
es
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Universidad Andrés Bello
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Licencia CC
Licencia CC
Resumen
La transfección de ácidos nucleicos es una técnica relevante que permite el ingreso de material genético en las células, lo que abre puertas a la modificación génica incluyendo, expresión, inhibición y por ende terapias génicas de carácter terapéutico. Los vectores no virales han ganado reconocimiento debido a su baja inmunogenicidad y su potencial para ser utilizados de manera más segura en la terapia génica. Sin embargo, cuando se trabaja con ácidos nucleicos que no son convencionales como el siRNA, la elección de un vector adecuado presenta desafíos, ya que no todos son capaces de cumplir con los requisitos necesarios. En este contexto, los péptidos anfifílicos (PAs) surgen como candidatos prometedores para la entrega eficaz de ácidos nucleicos, como el siRNA, Su habilidad de autoensamblaje y síntesis sencilla destaca su potencial en este ámbito. Considerando esto, en este proyecto se propone como objetivo diseñar un péptido autoensamblable capaz de unirse eficientemente ácidos nucleicos, utilizando simulaciones de dinámica molecular. Para esto se utilizó el péptido autoensamblable FA32 y se buscó mejorar su afinidad de unión a ácidos nucleicos, mediante su modificación y adición de Arg, debido a la carga hidrofílica positiva de este aminoácido, la cual puede facilitar interacciones fuertes con los grupos fosfato cargados negativamente de los ácidos nucleicos. Para realizar este diseño de péptido se utilizaron simulaciones de dinámica molecular de grano grueso, para poder así estudiar el autoensamblaje de FA32 y sus interacciones con el ácido nucleico, generando las modificaciones que harán que aumente su eficiencia al unirse a la biomolécula de interés.
Nucleic acid transfection is an advantageous technique that allows the entry of genetic material into the cells, which opens the doors to gene modification including, expression, inhibition, and thus therapeutic gene therapies. Non-viral vectors have gained recognition due to their low immunogenicity and potential to be used more safely in the gene therapy. However, when working with unconventional nucleic acids such as siRNA, the choice of the appropriate vector becomes problematic because not any vector can perform in an appropriate way, this is where the peptides amphiphiles (PAs) have emerged as promising candidates for the delivery of nucleic acids, such as the siRNA, given their ability of self-assembly and simple synthesis. Considering this, this project aims to design a self-assembly peptide capable of efficiently binding nucleic acids, using molecular dynamics simulations. For this purpose, the self-assembling peptide FA32 was used as a starting point and it improved the affinity by modification and addition of arginine, due to the hydrophilic charge of this amino acid, which can facilitate strong interactions with the negatively charged phosphate groups of the nucleic acids. To perform this peptide design coarse grain molecular dynamics simulations was used to study the self-assembly of the peptide FA32 and its interactions with a nucleic acid, to generate the modifications than made the increase the union efficiency binding to a biomolecule of interest.
Nucleic acid transfection is an advantageous technique that allows the entry of genetic material into the cells, which opens the doors to gene modification including, expression, inhibition, and thus therapeutic gene therapies. Non-viral vectors have gained recognition due to their low immunogenicity and potential to be used more safely in the gene therapy. However, when working with unconventional nucleic acids such as siRNA, the choice of the appropriate vector becomes problematic because not any vector can perform in an appropriate way, this is where the peptides amphiphiles (PAs) have emerged as promising candidates for the delivery of nucleic acids, such as the siRNA, given their ability of self-assembly and simple synthesis. Considering this, this project aims to design a self-assembly peptide capable of efficiently binding nucleic acids, using molecular dynamics simulations. For this purpose, the self-assembling peptide FA32 was used as a starting point and it improved the affinity by modification and addition of arginine, due to the hydrophilic charge of this amino acid, which can facilitate strong interactions with the negatively charged phosphate groups of the nucleic acids. To perform this peptide design coarse grain molecular dynamics simulations was used to study the self-assembly of the peptide FA32 and its interactions with a nucleic acid, to generate the modifications than made the increase the union efficiency binding to a biomolecule of interest.
Notas
Tesis (Licenciado en Biología)
Palabras clave
Transfección, Terapia Genética, Ácidos Nucleicos, Biotecnología, Dinámica Molecular, Simulación por Computadores.