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Pequeñas moléculas de bajo peso molecular pueden unirse potencialmente al ARN y afectar las vías oncogénicas en las
Blessy M Suresh1, Yoshihiro Akahori1, Amirhossein Taghavi1
1Department of Chemistry, The Scripps Research Institute & UF Scripps Biomedical Research, 130 Scripps Way, Jupiter, Florida 33458, United States.
Journal of the American Chemical Society
|November 2, 2022
Resumen
Los investigadores desarrollaron una nueva plataforma y una gran biblioteca de fragmentos para atacar el ARN con moléculas pequeñas. Se identificó un fragmento parecido a un fármaco que inhibe potentemente el procesamiento del microARN-372, reduciendo los fenotipos de las células de cáncer gástrico.
Área de la Ciencia:
- La bioquímica
- Biología molecular
- Química medicinal
Sus antecedentes:
- Dirigirse al ARN con moléculas pequeñas, especialmente de bajo peso molecular, presenta desafíos significativos para lograr una afinidad y especificidad suficientes.
- El desarrollo de nuevas interacciones bioactivas con el ARN es crucial para los avances terapéuticos.
Objetivo del estudio:
- Desarrollar una plataforma para la identificación de pequeñas moléculas que pueden atacar eficazmente el ARN.
- Descubrir y caracterizar un nuevo fragmento bioactivo capaz de modulación específica del ARN.
Principales métodos:
- Construcción de una colección de fragmentos de moléculas pequeñas enfocada en el ARN de 2500 compuestos.
- Utilizando la selección biblioteca-contra-biblioteca contra una biblioteca de ARN para sondear más de 12,8 millones de interacciones entre fragmentos de ARN.
- Minería de datos de interacción a través del transcriptoma humano para identificar fragmentos similares a las drogas.
Principales resultados:
- Identificación de un fragmento parecido a un fármaco con un enfoque potente y específico del precursor del microARN-372.
- Demostración de la inhibición del procesamiento del microARN y el alivio de los fenotipos oncogénicos en las células de cáncer gástrico.
- Caracterización de las propiedades favorables del fragmento: afinidad de 300 ± 130 nM, peso molecular de 273 Da y una puntuación QED de 0,8.
Conclusiones:
- Un compuesto de bajo peso molecular, similar a un fragmento, puede modular de manera específica y potente los objetivos de ARN.
- La plataforma desarrollada permite el descubrimiento de nuevas moléculas bioactivas dirigidas al ARN.
- Este enfoque es prometedor para el desarrollo de nuevas terapias contra enfermedades que involucran objetivos específicos de ARN.
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