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Translation of the intrinsically disordered protein α-synuclein is inhibited by a small molecule targeting its structured mRNA

Many proteins are refractory to targeting because they lack small-molecule binding pockets. An alternative to drugging these proteins directly is to target the messenger (m)RNA that encodes them, thereby reducing protein levels. We describe such an approach for the difficult-to-target protein α-synu...

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Autores principales: Zhang, Peiyuan, Park, Hye-Jin, Zhang, Jie, Junn, Eunsung, Andrews, Ryan J., Velagapudi, Sai Pradeep, Abegg, Daniel, Vishnu, Kamalakannan, Costales, Matthew G., Childs-Disney, Jessica L., Adibekian, Alexander, Moss, Walter N., Mouradian, M. Maral, Disney, Matthew D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983430/
https://www.ncbi.nlm.nih.gov/pubmed/31900363
http://dx.doi.org/10.1073/pnas.1905057117
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author Zhang, Peiyuan
Park, Hye-Jin
Zhang, Jie
Junn, Eunsung
Andrews, Ryan J.
Velagapudi, Sai Pradeep
Abegg, Daniel
Vishnu, Kamalakannan
Costales, Matthew G.
Childs-Disney, Jessica L.
Adibekian, Alexander
Moss, Walter N.
Mouradian, M. Maral
Disney, Matthew D.
author_facet Zhang, Peiyuan
Park, Hye-Jin
Zhang, Jie
Junn, Eunsung
Andrews, Ryan J.
Velagapudi, Sai Pradeep
Abegg, Daniel
Vishnu, Kamalakannan
Costales, Matthew G.
Childs-Disney, Jessica L.
Adibekian, Alexander
Moss, Walter N.
Mouradian, M. Maral
Disney, Matthew D.
author_sort Zhang, Peiyuan
collection PubMed
description Many proteins are refractory to targeting because they lack small-molecule binding pockets. An alternative to drugging these proteins directly is to target the messenger (m)RNA that encodes them, thereby reducing protein levels. We describe such an approach for the difficult-to-target protein α-synuclein encoded by the SNCA gene. Multiplication of the SNCA gene locus causes dominantly inherited Parkinson’s disease (PD), and α-synuclein protein aggregates in Lewy bodies and Lewy neurites in sporadic PD. Thus, reducing the expression of α-synuclein protein is expected to have therapeutic value. Fortuitously, the SNCA mRNA has a structured iron-responsive element (IRE) in its 5′ untranslated region (5′ UTR) that controls its translation. Using sequence-based design, we discovered small molecules that target the IRE structure and inhibit SNCA translation in cells, the most potent of which is named Synucleozid. Both in vitro and cellular profiling studies showed Synucleozid directly targets the α-synuclein mRNA 5′ UTR at the designed site. Mechanistic studies revealed that Synucleozid reduces α-synuclein protein levels by decreasing the amount of SNCA mRNA loaded into polysomes, mechanistically providing a cytoprotective effect in cells. Proteome- and transcriptome-wide studies showed that the compound’s selectivity makes Synucleozid suitable for further development. Importantly, transcriptome-wide analysis of mRNAs that encode intrinsically disordered proteins revealed that each has structured regions that could be targeted with small molecules. These findings demonstrate the potential for targeting undruggable proteins at the level of their coding mRNAs. This approach, as applied to SNCA, is a promising disease-modifying therapeutic strategy for PD and other α-synucleinopathies.
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spelling pubmed-69834302020-01-30 Translation of the intrinsically disordered protein α-synuclein is inhibited by a small molecule targeting its structured mRNA Zhang, Peiyuan Park, Hye-Jin Zhang, Jie Junn, Eunsung Andrews, Ryan J. Velagapudi, Sai Pradeep Abegg, Daniel Vishnu, Kamalakannan Costales, Matthew G. Childs-Disney, Jessica L. Adibekian, Alexander Moss, Walter N. Mouradian, M. Maral Disney, Matthew D. Proc Natl Acad Sci U S A PNAS Plus Many proteins are refractory to targeting because they lack small-molecule binding pockets. An alternative to drugging these proteins directly is to target the messenger (m)RNA that encodes them, thereby reducing protein levels. We describe such an approach for the difficult-to-target protein α-synuclein encoded by the SNCA gene. Multiplication of the SNCA gene locus causes dominantly inherited Parkinson’s disease (PD), and α-synuclein protein aggregates in Lewy bodies and Lewy neurites in sporadic PD. Thus, reducing the expression of α-synuclein protein is expected to have therapeutic value. Fortuitously, the SNCA mRNA has a structured iron-responsive element (IRE) in its 5′ untranslated region (5′ UTR) that controls its translation. Using sequence-based design, we discovered small molecules that target the IRE structure and inhibit SNCA translation in cells, the most potent of which is named Synucleozid. Both in vitro and cellular profiling studies showed Synucleozid directly targets the α-synuclein mRNA 5′ UTR at the designed site. Mechanistic studies revealed that Synucleozid reduces α-synuclein protein levels by decreasing the amount of SNCA mRNA loaded into polysomes, mechanistically providing a cytoprotective effect in cells. Proteome- and transcriptome-wide studies showed that the compound’s selectivity makes Synucleozid suitable for further development. Importantly, transcriptome-wide analysis of mRNAs that encode intrinsically disordered proteins revealed that each has structured regions that could be targeted with small molecules. These findings demonstrate the potential for targeting undruggable proteins at the level of their coding mRNAs. This approach, as applied to SNCA, is a promising disease-modifying therapeutic strategy for PD and other α-synucleinopathies. National Academy of Sciences 2020-01-21 2020-01-03 /pmc/articles/PMC6983430/ /pubmed/31900363 http://dx.doi.org/10.1073/pnas.1905057117 Text en Copyright © 2020 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle PNAS Plus
Zhang, Peiyuan
Park, Hye-Jin
Zhang, Jie
Junn, Eunsung
Andrews, Ryan J.
Velagapudi, Sai Pradeep
Abegg, Daniel
Vishnu, Kamalakannan
Costales, Matthew G.
Childs-Disney, Jessica L.
Adibekian, Alexander
Moss, Walter N.
Mouradian, M. Maral
Disney, Matthew D.
Translation of the intrinsically disordered protein α-synuclein is inhibited by a small molecule targeting its structured mRNA
title Translation of the intrinsically disordered protein α-synuclein is inhibited by a small molecule targeting its structured mRNA
title_full Translation of the intrinsically disordered protein α-synuclein is inhibited by a small molecule targeting its structured mRNA
title_fullStr Translation of the intrinsically disordered protein α-synuclein is inhibited by a small molecule targeting its structured mRNA
title_full_unstemmed Translation of the intrinsically disordered protein α-synuclein is inhibited by a small molecule targeting its structured mRNA
title_short Translation of the intrinsically disordered protein α-synuclein is inhibited by a small molecule targeting its structured mRNA
title_sort translation of the intrinsically disordered protein α-synuclein is inhibited by a small molecule targeting its structured mrna
topic PNAS Plus
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983430/
https://www.ncbi.nlm.nih.gov/pubmed/31900363
http://dx.doi.org/10.1073/pnas.1905057117
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