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    Features of Modularly Assembled Compounds That Impart Bioactivity Against an RNA Target
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    † Department of Chemistry, The Scripps Research Institute, Scripps Florida, 130 Scripps Way #3A1, Jupiter, Florida 33458, United States
    ‡ Department of Neurology, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642, United States
    *E-mail: [email protected]
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    ACS Chemical Biology

    Cite this: ACS Chem. Biol. 2013, 8, 10, 2312–2321
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    https://doi.org/10.1021/cb400265y
    Published September 13, 2013
    Copyright © 2013 American Chemical Society
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    Abstract

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    Transcriptomes provide a myriad of potential RNAs that could be the targets of therapeutics or chemical genetic probes of function. Cell-permeable small molecules, however, generally do not exploit these targets, owing to the difficulty in the design of high affinity, specific small molecules targeting RNA. As part of a general program to study RNA function using small molecules, we designed bioactive, modularly assembled small molecules that target the noncoding expanded RNA repeat that causes myotonic dystrophy type 1 (DM1), r(CUG)exp. Herein, we present a rigorous study to elucidate features in modularly assembled compounds that afford bioactivity. Different modular assembly scaffolds were investigated, including polyamines, α-peptides, β-peptides, and peptide tertiary amides (PTAs). On the basis of activity as assessed by improvement of DM1-associated defects, stability against proteases, cellular permeability, and toxicity, we discovered that constrained backbones, namely, PTAs, are optimal. Notably, we determined that r(CUG)exp is the target of the optimal PTA in cellular models and that the optimal PTA improves DM1-associated defects in a mouse model. Biophysical analyses were employed to investigate potential sources of bioactivity. These investigations show that modularly assembled compounds have increased residence times on their targets and faster on rates than the RNA-binding modules from which they were derived. Moreover, they have faster on rates than the protein that binds r(CUG)exp, the inactivation of which gives rise to DM1-associated defects. These studies provide information about features of small molecules that are programmable for targeting RNA, allowing for the facile optimization of therapeutics or chemical probes against other cellular RNA targets.

    Copyright © 2013 American Chemical Society

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    Synthetic procedures, compound characterization, experimental procedures, representative gel images, representative flow cytometry analyses, and supplementary tables and figures. This material is available free of charge via the Internet at http://pubs.acs.org.

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    This article is cited by 36 publications.

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    29. Alex C. Koon, Ho Yin Edwin Chan. Drosophila melanogaster As a Model Organism to Study RNA Toxicity of Repeat Expansion-Associated Neurodegenerative and Neuromuscular Diseases. Frontiers in Cellular Neuroscience 2017, 11 https://doi.org/10.3389/fncel.2017.00070
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    37. Jessica E. Wynn, Webster L. Santos. HIV-1 drug discovery: targeting folded RNA structures with branched peptides. Organic & Biomolecular Chemistry 2015, 13 (21) , 5848-5858. https://doi.org/10.1039/C5OB00589B
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    Cite this: ACS Chem. Biol. 2013, 8, 10, 2312–2321
    Click to copy citationCitation copied!
    https://doi.org/10.1021/cb400265y
    Published September 13, 2013
    Copyright © 2013 American Chemical Society
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