Cargando…
Principles for targeting RNA with drug-like small molecules
RNA molecules are essential for cellular information transfer and gene regulation, and RNAs have been implicated in many human diseases. Messenger and non-coding RNAs contain highly structured elements, and evidence suggests that many of these structures are important for function. Targeting these R...
Autores principales: | , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420209/ https://www.ncbi.nlm.nih.gov/pubmed/29977051 http://dx.doi.org/10.1038/nrd.2018.93 |
_version_ | 1783404066140848128 |
---|---|
author | Warner, Katherine Deigan Hajdin, Christine E. Weeks, Kevin M. |
author_facet | Warner, Katherine Deigan Hajdin, Christine E. Weeks, Kevin M. |
author_sort | Warner, Katherine Deigan |
collection | PubMed |
description | RNA molecules are essential for cellular information transfer and gene regulation, and RNAs have been implicated in many human diseases. Messenger and non-coding RNAs contain highly structured elements, and evidence suggests that many of these structures are important for function. Targeting these RNAs with small molecules offers opportunities to therapeutically modulate numerous cellular processes, including those linked to 'undruggable' protein targets. Despite this promise, there is currently only a single class of human-designed small molecules that target RNA used clinically — the linezolid antibiotics. However, a growing number of small-molecule RNA ligands are being identified, leading to burgeoning interest in the field. Here, we discuss principles for discovering small-molecule drugs that target RNA and argue that the overarching challenge is to identify appropriate target structures — namely, in disease-causing RNAs that have high information content and, consequently, appropriate ligand-binding pockets. If focus is placed on such druggable binding sites in RNA, extensive knowledge of the typical physicochemical properties of drug-like small molecules could then enable small-molecule drug discovery for RNA targets to become (only) roughly as difficult as for protein targets. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/nrd.2018.93) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6420209 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-64202092019-08-01 Principles for targeting RNA with drug-like small molecules Warner, Katherine Deigan Hajdin, Christine E. Weeks, Kevin M. Nat Rev Drug Discov Article RNA molecules are essential for cellular information transfer and gene regulation, and RNAs have been implicated in many human diseases. Messenger and non-coding RNAs contain highly structured elements, and evidence suggests that many of these structures are important for function. Targeting these RNAs with small molecules offers opportunities to therapeutically modulate numerous cellular processes, including those linked to 'undruggable' protein targets. Despite this promise, there is currently only a single class of human-designed small molecules that target RNA used clinically — the linezolid antibiotics. However, a growing number of small-molecule RNA ligands are being identified, leading to burgeoning interest in the field. Here, we discuss principles for discovering small-molecule drugs that target RNA and argue that the overarching challenge is to identify appropriate target structures — namely, in disease-causing RNAs that have high information content and, consequently, appropriate ligand-binding pockets. If focus is placed on such druggable binding sites in RNA, extensive knowledge of the typical physicochemical properties of drug-like small molecules could then enable small-molecule drug discovery for RNA targets to become (only) roughly as difficult as for protein targets. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/nrd.2018.93) contains supplementary material, which is available to authorized users. Nature Publishing Group UK 2018-07-06 2018 /pmc/articles/PMC6420209/ /pubmed/29977051 http://dx.doi.org/10.1038/nrd.2018.93 Text en © Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. 2018 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. |
spellingShingle | Article Warner, Katherine Deigan Hajdin, Christine E. Weeks, Kevin M. Principles for targeting RNA with drug-like small molecules |
title | Principles for targeting RNA with drug-like small molecules |
title_full | Principles for targeting RNA with drug-like small molecules |
title_fullStr | Principles for targeting RNA with drug-like small molecules |
title_full_unstemmed | Principles for targeting RNA with drug-like small molecules |
title_short | Principles for targeting RNA with drug-like small molecules |
title_sort | principles for targeting rna with drug-like small molecules |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420209/ https://www.ncbi.nlm.nih.gov/pubmed/29977051 http://dx.doi.org/10.1038/nrd.2018.93 |
work_keys_str_mv | AT warnerkatherinedeigan principlesfortargetingrnawithdruglikesmallmolecules AT hajdinchristinee principlesfortargetingrnawithdruglikesmallmolecules AT weekskevinm principlesfortargetingrnawithdruglikesmallmolecules |