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Design of a Bioactive Small Molecule That Targets R(AUUCU) Repeats in Spinocerebellar Ataxia 10

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Design of a Bioactive Small Molecule That Targets R(AUUCU) Repeats in Spinocerebellar Ataxia 10 ARTICLE Received 24 Jun 2015 | Accepted 18 Apr 2016 | Published 1 Jun 2016 DOI: 10.1038/ncomms11647 OPEN Design of a bioactive small molecule that targets r(AUUCU) repeats in spinocerebellar ataxia 10 Wang-Yong Yang1, Rui Gao2, Mark Southern3, Partha S. Sarkar2 & Matthew D. Disney1 RNA is an important target for chemical probes of function and lead therapeutics; however, it is difficult to target with small molecules. One approach to tackle this problem is to identify compounds that target RNA structures and utilize them to multivalently target RNA. Here we show that small molecules can be identified to selectively bind RNA base pairs by probing a library of RNA-focused small molecules. A small molecule that selectively binds AU base pairs informed design of a dimeric compound (2AU-2) that targets the pathogenic RNA, expanded r(AUUCU) repeats, that causes spinocerebellar ataxia type 10 (SCA10) in patient- derived cells. Indeed, 2AU-2 (50 nM) ameliorates various aspects of SCA10 pathology including improvement of mitochondrial dysfunction, reduced activation of caspase 3, and reduction of nuclear foci. These studies provide a first-in-class chemical probe to study SCA10 RNA toxicity and potentially define broadly applicable compounds targeting RNA AU base pairs in cells. 1 Departments of Chemistry and Neuroscience, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA. 2 Mitchell Center for Neurodegenerative Disorders, Department of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas 77555, USA. 3 Informatics Core, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA. Correspondence and requests for materials should be addressed to M.D.D. (email: [email protected]). NATURE COMMUNICATIONS | 7:11647 | DOI: 10.1038/ncomms11647 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms11647 NA has diverse cellular functions. For example, messenger further restrained to be fluorescent to allow for easy screening of RNAs (mRNAs) encode protein, microRNAs regulate the binding events, affording 104 small molecules (Fig. 1a and Rlifetime of mRNAs, and the ribosome translates mRNAs Supplementary Table 1). into proteins1,2. In bacteria, riboswitches control the production Compounds were screened for binding to different base pairs of proteins by binding to small molecule metabolites3,4. In fact, using four model constructs with stretches of AU and GC base many non-coding RNAs have been found to play significant roles pairs embedded in the stem of a common hairpin loop (Fig. 1b). in cellular biology, and these discoveries expand even further the The four RNAs display AU or GC pairs with different known functions of RNA5. nearest neighbours. AUAU and AAUU RNAs have 50AU/30UA Because of the important cellular functions of RNA under or 50AAUU/30UUAA stretches, respectively, while GCGC and normal conditions, it is not surprising that mutations in RNA can GGCC have 50GC/30CG or 50GGCC/30CCGG stretches, respec- cause disease. Single-nucleotide polymorphisms can give rise to tively. Due to significant differences in the thermodynamic cryptic alternative pre-mRNA splicing sites, leading to production stability of the hairpins, RNAs with AU pairs had 12 base pairs in of aberrant, defective proteins, as is the case with b-thalassae- the stem while RNAs with GC pairs had 8 (ref. 25). The DG°37 for mia6,7. Expanded RNA repeats can also contribute to disease and AUAU and AAUU is À 8.5 and À 6.7 kcal mol À 1, respectively, can be present in 50 and 30 untranslated regions (UTRs; while for GCGC and GGCC it is À 17.5 and À 19.1 kcal mol À 1, fragile X-associated tremor ataxia syndrome (FXTAS)8 and respectively. If only eight AU base pairs were present, then the myotonic dystrophy type 1 (DM1)9), introns (spinocerebellar free energy drops considerably to À 3.7 and À 2.5 kcal mol À 1, ataxia type 10 (SCA10)10 and myotonic dystrophy type 2 respectively. (DM2)11) or coding regions (Huntington’s disease (HD)12). In initial compound screens, each small molecule was Small molecules that target these RNA and inhibit its dysfunction incubated with the four RNAs and the change in emission was are thus highly desirable. measured (Fig. 1c). Changes in emission were not only analysed The bacterial ribosome is the most widely exploited RNA for statistical significance for binding to these RNAs in general, target13,14. Ribosomes and ribosomal RNA (rRNA) are privileged but also for binding to the different RNA structures. For targets as (i) ribosomes play essential roles in cellular homeostasis this compound collection, 29% of the compounds exhibited a and modulation of ribosome activity can have drastic cellular consequences, and (ii) rRNA comprises about 80–90% of the total 15 RNA content of a cell . Riboswitches are also emerging and a established targets of RNA-directed small molecules. Compounds H NH identified to bind to and modulate riboswitches generally mimic N RNA NH2 3,16 N focused the structure of the RNA’s natural metabolite , akin to H 17 N compound NH H N substrate mimicry to design enzyme inhibitors . Most RNA 2 2 N library N targets to which a small molecule binder is desired, however, HN H N H H are of low abundance and have no natural metabolite to inform N N N N H2N drug design. N N N Et cetera To aid RNA-targeting endeavours, our group has developed two-dimensional combinatorial screening (2DCS) to identify b AA AA AA AA optimal (high affinity and selective) RNA motif–small molecule GAGAGAGA interactions. These interactions are deposited into a database U-A U-A C-G C-G U-A A-U C-G G-C and can be used to design small molecules to target RNAs A-U U-A G-C C-G Test for AU A-U A-U G-C G-C selective by comparing motifs in the desired target to the database. U-A U-A C-G C-G This approach has been used to design small molecules targeting U-A A-U C-G G-C binding 18–20 21 22 A-U U-A G-C C-G UA the RNAs that cause DM , FXTAS and HD . All of the A-U A-U G-C G-C interactions that are presently in the RNA motif–small molecule U-A U-A 5′ 3′ 5′ 3′ U-A A-U GGCC GCGC GC database are between small molecules and RNA loops such as A-U U-A A-U A-U hairpins, bulges and internal loops. Herein, we report small 5′ 3′ 5′ 3′ molecules that bind selectively to RNA base pairs. Among a AAUU AUAU variety of compounds tested, small molecules with benzamidine moieties were identified to bind selectively to AU base pairs. c These data were leveraged to design the first bioactive small AAUU AUAU molecule to target the expanded r(AUUCU) repeat that causes GGCC SCA10, an incurable neuromuscular disorder. The compound GCGC exp 0 targets the central AU base pairs in r(AUUCU) and its dimeric 1 compound (2AU-2) displaces sequestered proteins and improves F/F defects in patient-derived cells. The observation that base pair- binding modules can provide bioactive compounds suggests that many other RNAs can be exploited as targets of small molecules. 0 10203040506070 80 90 100 Compound Figure 1 | Overall scheme to identify small molecules that bind to RNA Results and Discussion base pairs. (a) A small molecule library was collected in which the small Binding of RNA-focused small molecules to RNA base pairs. molecules have chemotypes present in compounds known to bind RNA. By using chemical similarity searching, small molecules with (b) The RNA-focused small molecule library was tested for binding to four features that should pre-dispose them for binding RNA23,24 were different RNAs that have different orientations and identities of RNA base collected from both the National Cancer Institute’s and The pairs. (c) Compounds were tested in a fluorescence emission assay for Scripps Research Institute’s chemical libraries, including selectively binding to RNAs with different paired elements. Compounds that benzimidazole, benzamidine, aniline moieties. Compounds were were selective were further analysed. 2 NATURE COMMUNICATIONS | 7:11647 | DOI: 10.1038/ncomms11647 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | DOI: 10.1038/ncomms11647 ARTICLE change in emission upon binding to any of the RNAs used in Compounds 1 and 2 bind selectively to AU base pairs. The this study, and 18% of the compounds showed preferential selectivities of compounds 1 and 2 were further assessed by binding to AU or GC pair-containing duplexes (Supplementary measuring EC50s for all four RNAs. The EC50s for 1 for binding Table 2). to AAUU, AUAU, GGCC and GCGC are 170, 45, 390 and On the basis of the substructures within compounds that bind, 240 nM, respectively, while the EC50’s for 2 are 170, 190, 8,550 a Venn diagram was constructed to correlate chemotypes and and 6,950 nM, respectively (Table 1). On the basis of these data, 2 binding to AU and GC base pairs (Fig. 2). For example, various is much more selective for AU base pairs than 1, with an AU pair B functionalized purines bound to RNAs with GC base pairs. selectivity of 40-fold (Fig. 3). Measurement of the Kd’s of 2 to Previously, other compounds that bind RNA base pairs have been AUAU and AAUU give values of 210 and 320 nM, respectively, identified. For example, the Beal group has used threading and stoichiometries of 2.9 and 3.7, respectively (Supplementary intercalators with acridine or other aromatic functionalities to Fig. 4). These data suggests that 2 is a high affinity binder to target RNA bulges with nearby GC pairs26.
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