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Inhibition of the Eukaryotic 80S Ribosome as a Potential Anticancer Therapy: A Structural Perspective

SIMPLE SUMMARY: Unravelling the molecular basis of ribosomal inhibition by small molecules is crucial to characterise the function of potential anticancer drugs. After approval of the ribosome inhibitor homoharringtonine for treatment of CML, it became clear that acting on the rate of protein synthe...

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Autores principales: Pellegrino, Simone, Terrosu, Salvatore, Yusupova, Gulnara, Yusupov, Marat
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430933/
https://www.ncbi.nlm.nih.gov/pubmed/34503202
http://dx.doi.org/10.3390/cancers13174392
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author Pellegrino, Simone
Terrosu, Salvatore
Yusupova, Gulnara
Yusupov, Marat
author_facet Pellegrino, Simone
Terrosu, Salvatore
Yusupova, Gulnara
Yusupov, Marat
author_sort Pellegrino, Simone
collection PubMed
description SIMPLE SUMMARY: Unravelling the molecular basis of ribosomal inhibition by small molecules is crucial to characterise the function of potential anticancer drugs. After approval of the ribosome inhibitor homoharringtonine for treatment of CML, it became clear that acting on the rate of protein synthesis can be a valuable way to prevent indefinite growth of cancers. The present review discusses the state-of-the-art structural knowledge of the binding modes of inhibitors targeting the cytosolic ribosome, with the ambition of providing not only an overview of what has been achieved so far, but to stimulate further investigations to yield more potent and specific anticancer drugs. ABSTRACT: Protein biosynthesis is a vital process for all kingdoms of life. The ribosome is the massive ribonucleoprotein machinery that reads the genetic code, in the form of messenger RNA (mRNA), to produce proteins. The mechanism of translation is tightly regulated to ensure that cell growth is well sustained. Because of the central role fulfilled by the ribosome, it is not surprising that halting its function can be detrimental and incompatible with life. In bacteria, the ribosome is a major target of inhibitors, as demonstrated by the high number of small molecules identified to bind to it. In eukaryotes, the design of ribosome inhibitors may be used as a therapy to treat cancer cells, which exhibit higher proliferation rates compared to healthy ones. Exciting experimental achievements gathered during the last few years confirmed that the ribosome indeed represents a relevant platform for the development of anticancer drugs. We provide herein an overview of the latest structural data that helped to unveil the molecular bases of inhibition of the eukaryotic ribosome triggered by small molecules.
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spelling pubmed-84309332021-09-11 Inhibition of the Eukaryotic 80S Ribosome as a Potential Anticancer Therapy: A Structural Perspective Pellegrino, Simone Terrosu, Salvatore Yusupova, Gulnara Yusupov, Marat Cancers (Basel) Review SIMPLE SUMMARY: Unravelling the molecular basis of ribosomal inhibition by small molecules is crucial to characterise the function of potential anticancer drugs. After approval of the ribosome inhibitor homoharringtonine for treatment of CML, it became clear that acting on the rate of protein synthesis can be a valuable way to prevent indefinite growth of cancers. The present review discusses the state-of-the-art structural knowledge of the binding modes of inhibitors targeting the cytosolic ribosome, with the ambition of providing not only an overview of what has been achieved so far, but to stimulate further investigations to yield more potent and specific anticancer drugs. ABSTRACT: Protein biosynthesis is a vital process for all kingdoms of life. The ribosome is the massive ribonucleoprotein machinery that reads the genetic code, in the form of messenger RNA (mRNA), to produce proteins. The mechanism of translation is tightly regulated to ensure that cell growth is well sustained. Because of the central role fulfilled by the ribosome, it is not surprising that halting its function can be detrimental and incompatible with life. In bacteria, the ribosome is a major target of inhibitors, as demonstrated by the high number of small molecules identified to bind to it. In eukaryotes, the design of ribosome inhibitors may be used as a therapy to treat cancer cells, which exhibit higher proliferation rates compared to healthy ones. Exciting experimental achievements gathered during the last few years confirmed that the ribosome indeed represents a relevant platform for the development of anticancer drugs. We provide herein an overview of the latest structural data that helped to unveil the molecular bases of inhibition of the eukaryotic ribosome triggered by small molecules. MDPI 2021-08-31 /pmc/articles/PMC8430933/ /pubmed/34503202 http://dx.doi.org/10.3390/cancers13174392 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Pellegrino, Simone
Terrosu, Salvatore
Yusupova, Gulnara
Yusupov, Marat
Inhibition of the Eukaryotic 80S Ribosome as a Potential Anticancer Therapy: A Structural Perspective
title Inhibition of the Eukaryotic 80S Ribosome as a Potential Anticancer Therapy: A Structural Perspective
title_full Inhibition of the Eukaryotic 80S Ribosome as a Potential Anticancer Therapy: A Structural Perspective
title_fullStr Inhibition of the Eukaryotic 80S Ribosome as a Potential Anticancer Therapy: A Structural Perspective
title_full_unstemmed Inhibition of the Eukaryotic 80S Ribosome as a Potential Anticancer Therapy: A Structural Perspective
title_short Inhibition of the Eukaryotic 80S Ribosome as a Potential Anticancer Therapy: A Structural Perspective
title_sort inhibition of the eukaryotic 80s ribosome as a potential anticancer therapy: a structural perspective
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430933/
https://www.ncbi.nlm.nih.gov/pubmed/34503202
http://dx.doi.org/10.3390/cancers13174392
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