A Novel CUG<sup>exp</sup>·MBNL1 Inhibitor with Therapeutic Potential for Myotonic Dystrophy Type 1

Jahromi, Amin Haghighat; Nguyen, Lien; Fu, Yuan; Miller, Kali A.; Baranger, Anne M.; Zimmerman, Steven C.

doi:10.1021/cb400046u

Cited by 52 publications

(73 citation statements)

References 42 publications

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“…1,2 Although a small data set, selective RNA motif–small molecule interactions have been used to inform the design of bioactive small molecules, including monomeric and modularly assembled ligands. 3−13 The latter compounds bind RNAs that have multiple targetable motifs that are separated by a specific distance. 8,11 In order to target the myriad of disease-causing RNAs in a cell using rational and predictable methods, much more data that describe selective interactions between small molecules and RNA motifs will be required, as well as new high throughput tools and technologies to obtain them.…”

mentioning

confidence: 99%

Defining RNA–Small Molecule Affinity Landscapes Enables Design of a Small Molecule Inhibitor of an Oncogenic Noncoding RNA

et al. 2017

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RNA drug targets are pervasive in cells, but methods to design small molecules that target them are sparse. Herein, we report a general approach to score the affinity and selectivity of RNA motif–small molecule interactions identified via selection. Named High Throughput Structure–Activity Relationships Through Sequencing (HiT-StARTS), HiT-StARTS is statistical in nature and compares input nucleic acid sequences to selected library members that bind a ligand via high throughput sequencing. The approach allowed facile definition of the fitness landscape of hundreds of thousands of RNA motif–small molecule binding partners. These results were mined against folded RNAs in the human transcriptome and identified an avid interaction between a small molecule and the Dicer nuclease-processing site in the oncogenic microRNA (miR)-18a hairpin precursor, which is a member of the miR-17-92 cluster. Application of the small molecule, Targapremir-18a, to prostate cancer cells inhibited production of miR-18a from the cluster, de-repressed serine/threonine protein kinase 4 protein (STK4), and triggered apoptosis. Profiling the cellular targets of Targapremir-18a via Chemical Cross-Linking and Isolation by Pull Down (Chem-CLIP), a covalent small molecule–RNA cellular profiling approach, and other studies showed specific binding of the compound to the miR-18a precursor, revealing broadly applicable factors that govern small molecule drugging of noncoding RNAs.

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confidence: 99%

Defining RNA–Small Molecule Affinity Landscapes Enables Design of a Small Molecule Inhibitor of an Oncogenic Noncoding RNA

et al. 2017

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“…Finally, phase I and II clinical trials of a gapmer targeting mutant DMPK mRNA has been recently initiated (Isis Pharmaceuticals, 2014). A number of small molecule probes have also been developed for targeting r(CUG) exp that displace MBNL1 and improve downstream defects (Arambula et al, 2009; Childs-Disney et al, 2012a, 2012b, 2013; Hoskins et al, 2014; Jahromi et al, 2013a, 2013b; Parkesh et al, 2012). These compounds were either identified from screening, designed from the structure of r(CUG) repeats, or designed from privileged RNA motif-small molecule interactions including modularly assembled compounds thereof.…”

Section: Leveraging Rna Structure To Design Chemical Probes Of Functionmentioning

confidence: 99%

RNA Structures as Mediators of Neurological Diseases and as Drug Targets

Bernat

Disney

2015

Neuron

115

107

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RNAs adopt diverse folded structures that are essential for function and thus play critical roles in cellular biology. A striking example of this is the ribosome, a complex, three-dimensionally folded macromolecular machine that orchestrates protein synthesis. Advances in RNA biochemistry, structural and molecular biology, and bioinformatics have revealed other non-coding RNAs whose functions are dictated by their structure. It is not surprising that aberrantly folded RNA structures contribute to disease. In this review, we provide a brief introduction into RNA structural biology and then describe how RNA structures function in cells and cause or contribute to neurological disease. Finally, we highlight successful applications of rational design principles to provide chemical probes and lead compounds targeting structured RNAs. Based on several examples of well-characterized RNA-driven neurological disorders, we demonstrate how designed small molecules can facilitate study of RNA dysfunction, elucidating previously unknown roles for RNA in disease, and provide lead therapeutics.

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“…The bifacial symmetry of monosubstituted melamine allows recognition of a T-T or U-U site in DNA or RNA. 17,18 Melamine-displaying α-peptides (bifacial PNA or bPNA) bind to unstructured oligothymidine and oligouridylate tracts to form obligate triplex hybrid structures 19,20 by virtue of base-triple recognition and stacking ( Figure 1). This triplex interface can effectively compete with enzymatic processing of nucleic acids, 21 but can also serve as a structural trigger for noncoding DNA and RNA function 22 as well as peptidebond formation.…”

Section: Triazines and Dna Molecular Recognitionmentioning

confidence: 99%

Synthesis of DNA-Binding Peptoids

Mao

Bong

2015

Synlett

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Programmable molecular recognition through nucleic acid base pairing has enabled applications in nano-and biotechnology using DNA, RNA, PNA, and more recently, bifacial PNA (bPNA). We describe herein the synthesis and DNA recognition properties of peptoid backbones bearing the bifacial synthetic nucleobase melamine. These 'peptoid nucleic acids' hybridize with thymine-rich DNA, like their peptide cognate (bPNA). DNA complexation is highly sensitive to peptoid sidechain length and overall charge. Peptoids isomeric with peptide bPNA were less efficient at DNA recognition, possibly due to conformational and steric differences. 1Triazines and DNA Molecular Recognition 2Synthesis of DNA-Binding Peptoids 3Peptoid-DNA Binding Studies Triazines and DNA Molecular RecognitionComplexation of 1,3,5-triazines based on melamine and cyanuric acid have been well-studied in the solid state, 1-3 in organic solvents, 4,5 and in water. 1,6-13 Like DNA base stacking, 14 aqueous-phase triazine assembly is strongly exothermic. 6 Indeed, melamine derivatives can dock thymine 15 or uracil 16 bases via their Watson-Crick faces. The bifacial symmetry of monosubstituted melamine allows recognition of a T-T or U-U site in DNA or RNA. 17,18 Melamine-displaying α-peptides (bifacial PNA or bPNA) bind to unstructured oligothymidine and oligouridylate tracts to form obligate triplex hybrid structures 19,20 by virtue of base-triple recognition and stacking (Figure 1). This triplex interface can effectively compete with enzymatic processing of nucleic acids, 21 but can also serve as a structural trigger for noncoding DNA and RNA function 22 as well as peptidebond formation. 23 The structure of conventional PNA, 24 α-PNA, 25,26 and peptoids 27 are similar in their polyamide backbones as well as the spacing of nucleic acid interacting residues, which are separated by seven backbone atoms in each macromolecule. The absence of intervening side chains in conventional PNA leads to a neutral backbone, while alternate residues in α-PNA and peptoids afford an opportunity to tune electrostatic interactions and water solubility through installation of polar side chains. As potential biomedical reagents, the peptoid scaffold holds considerable appeal in increased protease stability. 28,29 Furthermore, as a result of the tertiary amide backbone, peptoids are much less polar than peptides composed of secondary amide linkages leading to increased transmembrane passage and intracellular delivery. 30 Herein we describe the synthesis of triazine-displaying peptoid macromolecules and their DNA-binding properties. We find peptoids to be less efficient in binding DNA relative to their peptide analogues.

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A Novel CUG^exp·MBNL1 Inhibitor with Therapeutic Potential for Myotonic Dystrophy Type 1

Cited by 52 publications

References 42 publications

Defining RNA–Small Molecule Affinity Landscapes Enables Design of a Small Molecule Inhibitor of an Oncogenic Noncoding RNA

Defining RNA–Small Molecule Affinity Landscapes Enables Design of a Small Molecule Inhibitor of an Oncogenic Noncoding RNA

RNA Structures as Mediators of Neurological Diseases and as Drug Targets

Synthesis of DNA-Binding Peptoids

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A Novel CUGexp·MBNL1 Inhibitor with Therapeutic Potential for Myotonic Dystrophy Type 1

Cited by 52 publications

References 42 publications

Defining RNA–Small Molecule Affinity Landscapes Enables Design of a Small Molecule Inhibitor of an Oncogenic Noncoding RNA

Defining RNA–Small Molecule Affinity Landscapes Enables Design of a Small Molecule Inhibitor of an Oncogenic Noncoding RNA

RNA Structures as Mediators of Neurological Diseases and as Drug Targets

Synthesis of DNA-Binding Peptoids

Contact Info

Product

Resources

About

A Novel CUG^exp·MBNL1 Inhibitor with Therapeutic Potential for Myotonic Dystrophy Type 1