Decreasing the intrinsically disordered protein α-synuclein levels by targeting its structured mRNA with a ribonuclease- targeting chimera

• 成果类型: Article
• 署名作者: Tong, Yuquan; Zhang, Peiyuan; Yang, Xueyi; Liu, Xiaohui; Zhang, Jie; Grudniewska, Magda; Jung, Ikrak; Abegg, Daniel; Liu, Jun; Childs-Disney, Jessica L.; Gibaut, Quentin M. R.; Haniff, Hafeez S.; Adibekian, Alexander; Mouradian, M. Maral; Disney, Matthew D.
• 署名单位: State University System of Florida; University of Florida; Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology; Rutgers University System; Rutgers University New Brunswick; Rutgers University Biomedical & Health Sciences; Rutgers University System; Rutgers University New Brunswick; Rutgers University Biomedical & Health Sciences
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12156
• DOI: 10.1073/pnas.2306682120
• 发表日期: 2024-01-09
• 关键词: small-molecule inhibition; sequence-based design; degradation; DISCOVERY; ubiquitination; therapeutics; protacs; kras

摘要

alpha-Synuclein is an important drug target for the treatment of Parkinson's disease (PD), but it is an intrinsically disordered protein lacking typical small-molecule binding pockets. In contrast, the encoding SNCA mRNA has regions of ordered structure in its 5 ' untranslated region (UTR). Here, we present an integrated approach to identify small molecules that bind this structured region and inhibit alpha-synuclein translation. A drug-like, RNA-focused compound collection was studied for binding to the 5 ' UTR of SNCA mRNA, affording Synucleozid-2.0, a drug-like small molecule that decreases alpha-synuclein levels by inhibiting ribosomes from assembling onto SNCA mRNA. This RNA-binding small molecule was converted into a ribonuclease-targeting chimera (RiboTAC) to degrade cellular SNCA mRNA. RNA-seq and proteomics studies demonstrated that the RiboTAC (Syn-RiboTAC) selectively degraded SNCA mRNA to reduce its protein levels, affording a fivefold enhancement of cytoprotective effects as compared to Synucleozid-2.0. As observed in many diseases, transcriptome-wide changes in RNA expression are observed in PD. Syn-RiboTAC also rescued the expression of similar to 50% of genes that were abnormally expressed in dopaminergic neurons differentiated from PD patient-derived iPSCs. These studies demonstrate that the druggability of the proteome can be expanded greatly by targeting the encoding mRNAs with both small molecule binders and RiboTAC degraders.