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Three main types of RNA are involved in protein synthesis: messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA). These RNAs perform diverse functions and can be broadly classified as protein-coding or non-coding RNA. Non-coding RNAs play important roles in the regulation of gene expression in response to developmental and environmental changes. Non-coding RNAs in prokaryotes can be manipulated to develop more effective antibacterial drugs for human or animal use.
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RNA Interference01:23

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RNA interference (RNAi) is a process in which a small non-coding RNA molecule blocks the post-transcriptional expression of a gene by binding to its messenger RNA (mRNA) and preventing the protein from being translated.
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RNA interference (RNAi) is a cellular mechanism that inhibits gene expression by suppressing its transcription or activating the RNA degradation process. The mechanism was discovered by Andrew Fire and Craig Mello in 1998 in plants. Today, it is observed in almost all eukaryotes, including protozoa, flies, nematodes, insects, parasites, and mammals. This precise cellular mechanism of gene silencing has been developed into a technique that provides an efficient way to identify and determine the...
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Small interfering RNAs, or siRNAs, are short regulatory RNA molecules that can silence genes post-transcriptionally, as well as the transcriptional level in some cases. siRNAs are important for protecting cells against viral infections and silencing transposable genetic elements.
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Before mRNAs are exported to the cytoplasm, it is crucial to check each mRNA for structural and functional integrity. Eukaryotic cells use several different mechanisms, collectively known as mRNA surveillance, to look for irregularities in mRNAs. Irregular or aberrant mRNA are rapidly degraded by various enzymes. If a defective mRNA escapes the surveillance, it would be translated into a protein which would either be non-functional or not function properly. One of the primary irregularities in...
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The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
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Using In Vitro and In-cell SHAPE to Investigate Small Molecule Induced Pre-mRNA Structural Changes
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Programación de pequeñas moléculas de unión al ARN inactivo en degradantes bioactivos

Yuquan Tong1, Yeongju Lee1, Xiaohui Liu1

  • 1Department of Chemistry, The Scripps Research Institute & The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA.

Nature
|May 24, 2023
PubMed
Resumen
Este resumen es generado por máquina.

Los investigadores exploraron cómo las moléculas pequeñas interactúan con el ARN, encontrando que muchas se unen débilmente. Desarrollaron un nuevo método para degradar el ARN objetivo utilizando estos enlaces, apuntando con éxito al microARN-155 y al ARNm relacionados con la enfermedad.

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Área de la Ciencia:

  • Biología molecular
  • Química medicinal
  • Terapia con ARN

Sus antecedentes:

  • La unión de moléculas pequeñas al ARN es un desafío para lograr actividad biológica.
  • Comprender las interacciones entre ARN y moléculas pequeñas es crucial para el descubrimiento de fármacos.

Objetivo del estudio:

  • Investigar patrones de reconocimiento molecular entre moléculas pequeñas y estructuras de ARN 3D.
  • Explorar estrategias para modular la biología del ARN utilizando moléculas pequeñas.
  • Desarrollar agentes degradantes dirigidos al ARN para aplicaciones terapéuticas.

Principales métodos:

  • Interacciones estudiadas entre una colección de moléculas pequeñas inspiradas en productos naturales y estructuras de ARN plegadas.
  • Mapa de paisajes de interacción de moléculas pequeñas de ARN a través del transcriptoma humano.
  • Químeras dirigidas a la ribonucleasa diseñadas para inducir la división del ARN.
  • Los degradantes validados para el microARN-155 precursor, el mRNA JUN y el mRNA MYC.

Principales resultados:

  • Se han identificado relaciones estructura-actividad para las interacciones entre ARN y moléculas pequeñas.
  • Se encontró que se predijo que la mayoría de las interacciones serían biológicamente inertes debido a la ubicación de unión.
  • Se demostró que los aglutinantes inactivos pueden convertirse en potentes degradantes de ARN.
  • Se han diseñado con éxito degradadores selectivos para objetivos específicos de ARN.

Conclusiones:

  • Las interacciones entre pequeñas moléculas y ARN se pueden aprovechar para la degradación dirigida del ARN.
  • Las quimeras dirigidas a la ribonucleasa ofrecen una estrategia para convertir los enlaces débiles en potentes moduladores de la función del ARN.
  • Este enfoque es prometedor para el desarrollo de nuevas terapias dirigidas al ARN.