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

Abstract

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.

• Authors: Peiyuan Zhang, Hye-Jin Park, Jie Zhang, Eunsung Junn, Ryan J Andrews, Sai Pradeep Velagapudi, Daniel Abegg, Kamalakannan Vishnu, Matthew G Costales, Jessica L Childs-Disney, Alexander Adibekian, Walter N Moss, M Maral Mouradian, Matthew D Disney
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 117 Issue 3 Pg. 1457-1467 (01 21 2020) ISSN: 1091-6490 [Electronic] United States
• PMID: 31900363 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 the Author(s). Published by PNAS.

Chemical References

• 3' Untranslated Regions
• Intrinsically Disordered Proteins
• Protein Synthesis Inhibitors
• RNA, Messenger
• alpha-Synuclein

Topics

• 3' Untranslated Regions
• Animals
• Cell Line, Tumor
• Humans
• Intrinsically Disordered Proteins (genetics, metabolism)
• Mice
• Protein Biosynthesis (drug effects)
• Protein Synthesis Inhibitors (chemistry, pharmacology)
• RNA, Messenger (chemistry, genetics, metabolism)
• Response Elements
• alpha-Synuclein (genetics, metabolism)