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Rationally designed inhibitors of the Musashi protein-RNA interaction by hotspot mimicry
RNA-binding proteins (RBPs) are key post-transcriptional regulators of gene expression, and thus underlie many important biological processes. Here, we developed a strategy that entails extracting a “hotspot pharmacophore” from the structure of a protein-RNA complex, to create a template for designi...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Journal Experts
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9882606/ https://www.ncbi.nlm.nih.gov/pubmed/36711552 http://dx.doi.org/10.21203/rs.3.rs-2395172/v1 |
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author | Bai, Nan Adeshina, Yusuf Bychkov, Igor Xia, Yan Gowthaman, Ragul Miller, Sven A. Gupta, Abhishek K. Johnson, David K. Lan, Lan Golemis, Erica A. Makhov, Petr B. Xu, Liang Pillai, Manoj M. Boumber, Yanis Karanicolas, John |
author_facet | Bai, Nan Adeshina, Yusuf Bychkov, Igor Xia, Yan Gowthaman, Ragul Miller, Sven A. Gupta, Abhishek K. Johnson, David K. Lan, Lan Golemis, Erica A. Makhov, Petr B. Xu, Liang Pillai, Manoj M. Boumber, Yanis Karanicolas, John |
author_sort | Bai, Nan |
collection | PubMed |
description | RNA-binding proteins (RBPs) are key post-transcriptional regulators of gene expression, and thus underlie many important biological processes. Here, we developed a strategy that entails extracting a “hotspot pharmacophore” from the structure of a protein-RNA complex, to create a template for designing small-molecule inhibitors and for exploring the selectivity of the resulting inhibitors. We demonstrate this approach by designing inhibitors of Musashi proteins MSI1 and MSI2, key regulators of mRNA stability and translation that are upregulated in many cancers. We report this novel series of MSI1/MSI2 inhibitors is specific and active in biochemical, biophysical, and cellular assays. This study extends the paradigm of “hotspots” from protein-protein complexes to protein-RNA complexes, supports the “druggability” of RNA-binding protein surfaces, and represents one of the first rationally-designed inhibitors of non-enzymatic RNA-binding proteins. Owing to its simplicity and generality, we anticipate that this approach may also be used to develop inhibitors of many other RNA-binding proteins; we also consider the prospects of identifying potential off-target interactions by searching for other RBPs that recognize their cognate RNAs using similar interaction geometries. Beyond inhibitors, we also expect that compounds designed using this approach can serve as warheads for new PROTACs that selectively degrade RNA-binding proteins. |
format | Online Article Text |
id | pubmed-9882606 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Journal Experts |
record_format | MEDLINE/PubMed |
spelling | pubmed-98826062023-01-28 Rationally designed inhibitors of the Musashi protein-RNA interaction by hotspot mimicry Bai, Nan Adeshina, Yusuf Bychkov, Igor Xia, Yan Gowthaman, Ragul Miller, Sven A. Gupta, Abhishek K. Johnson, David K. Lan, Lan Golemis, Erica A. Makhov, Petr B. Xu, Liang Pillai, Manoj M. Boumber, Yanis Karanicolas, John Res Sq Article RNA-binding proteins (RBPs) are key post-transcriptional regulators of gene expression, and thus underlie many important biological processes. Here, we developed a strategy that entails extracting a “hotspot pharmacophore” from the structure of a protein-RNA complex, to create a template for designing small-molecule inhibitors and for exploring the selectivity of the resulting inhibitors. We demonstrate this approach by designing inhibitors of Musashi proteins MSI1 and MSI2, key regulators of mRNA stability and translation that are upregulated in many cancers. We report this novel series of MSI1/MSI2 inhibitors is specific and active in biochemical, biophysical, and cellular assays. This study extends the paradigm of “hotspots” from protein-protein complexes to protein-RNA complexes, supports the “druggability” of RNA-binding protein surfaces, and represents one of the first rationally-designed inhibitors of non-enzymatic RNA-binding proteins. Owing to its simplicity and generality, we anticipate that this approach may also be used to develop inhibitors of many other RNA-binding proteins; we also consider the prospects of identifying potential off-target interactions by searching for other RBPs that recognize their cognate RNAs using similar interaction geometries. Beyond inhibitors, we also expect that compounds designed using this approach can serve as warheads for new PROTACs that selectively degrade RNA-binding proteins. American Journal Experts 2023-01-10 /pmc/articles/PMC9882606/ /pubmed/36711552 http://dx.doi.org/10.21203/rs.3.rs-2395172/v1 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. |
spellingShingle | Article Bai, Nan Adeshina, Yusuf Bychkov, Igor Xia, Yan Gowthaman, Ragul Miller, Sven A. Gupta, Abhishek K. Johnson, David K. Lan, Lan Golemis, Erica A. Makhov, Petr B. Xu, Liang Pillai, Manoj M. Boumber, Yanis Karanicolas, John Rationally designed inhibitors of the Musashi protein-RNA interaction by hotspot mimicry |
title | Rationally designed inhibitors of the Musashi protein-RNA interaction by hotspot mimicry |
title_full | Rationally designed inhibitors of the Musashi protein-RNA interaction by hotspot mimicry |
title_fullStr | Rationally designed inhibitors of the Musashi protein-RNA interaction by hotspot mimicry |
title_full_unstemmed | Rationally designed inhibitors of the Musashi protein-RNA interaction by hotspot mimicry |
title_short | Rationally designed inhibitors of the Musashi protein-RNA interaction by hotspot mimicry |
title_sort | rationally designed inhibitors of the musashi protein-rna interaction by hotspot mimicry |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9882606/ https://www.ncbi.nlm.nih.gov/pubmed/36711552 http://dx.doi.org/10.21203/rs.3.rs-2395172/v1 |
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