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Multiassay Profiling of a Focused Small Molecule Library Reveals Predictive Bidirectional Modulation of the lncRNA MALAT1 Triplex Stability In Vitro.

Publication ,  Journal Article
Zafferani, M; Martyr, JG; Muralidharan, D; Montalvan, NI; Cai, Z; Hargrove, AE
Published in: ACS chemical biology
September 2022

The rapidly accelerating characterization of RNA tertiary structures has revealed their pervasiveness and active roles in human diseases. Small molecule-mediated modulation of RNA tertiary structures constitutes an attractive avenue for the development of tools for therapeutically targeting and/or uncovering the pathways associated with these RNA motifs. This potential has been highlighted by targeting of the triple helix present at the 3'-end of the noncoding RNA MALAT1, a transcript implicated in several human diseases. This triplex has been reported to decrease the susceptibility of the transcript to degradation and promote its cellular accumulation. While small molecules have been shown to bind to and impact the stability of the MALAT1 triple helix, the small molecule properties that lead to these structural modulations are not well understood. We designed a library utilizing the diminazene scaffold, which is underexplored but precedented for nucleic acid binding, to target the MALAT1 triple helix. We employed multiple assays to holistically assess what parameters, if any, could predict the small molecule affinity and effect on triplex stability. We designed and/or optimized competition, calorimetry, and thermal shift assays as well as an enzymatic degradation assay, the latter of which led to the discovery of bidirectional modulators of triple helix stability within the scaffold-centric library. Determination of quantitative structure-activity relationships afforded predictive models for both affinity- and stability-based assays. This work establishes a suite of powerful orthogonal biophysical tools for the evaluation of small molecule:RNA triplex interactions that generate predictive models and will allow small molecule interrogation of the growing body of disease-associated RNA triple helices.

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Published In

ACS chemical biology

DOI

EISSN

1554-8937

ISSN

1554-8929

Publication Date

September 2022

Volume

17

Issue

9

Start / End Page

2437 / 2447

Related Subject Headings

  • RNA, Long Noncoding
  • Organic Chemistry
  • Nucleic Acid Conformation
  • Humans
  • Gene Library
  • Diminazene
  • Calorimetry
  • 34 Chemical sciences
  • 31 Biological sciences
  • 06 Biological Sciences
 

Citation

APA
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Zafferani, M., Martyr, J. G., Muralidharan, D., Montalvan, N. I., Cai, Z., & Hargrove, A. E. (2022). Multiassay Profiling of a Focused Small Molecule Library Reveals Predictive Bidirectional Modulation of the lncRNA MALAT1 Triplex Stability In Vitro. ACS Chemical Biology, 17(9), 2437–2447. https://doi.org/10.1021/acschembio.2c00124
Zafferani, Martina, Justin G. Martyr, Dhanasheel Muralidharan, Nadeska I. Montalvan, Zhengguo Cai, and Amanda E. Hargrove. “Multiassay Profiling of a Focused Small Molecule Library Reveals Predictive Bidirectional Modulation of the lncRNA MALAT1 Triplex Stability In Vitro.ACS Chemical Biology 17, no. 9 (September 2022): 2437–47. https://doi.org/10.1021/acschembio.2c00124.
Zafferani M, Martyr JG, Muralidharan D, Montalvan NI, Cai Z, Hargrove AE. Multiassay Profiling of a Focused Small Molecule Library Reveals Predictive Bidirectional Modulation of the lncRNA MALAT1 Triplex Stability In Vitro. ACS chemical biology. 2022 Sep;17(9):2437–47.
Zafferani, Martina, et al. “Multiassay Profiling of a Focused Small Molecule Library Reveals Predictive Bidirectional Modulation of the lncRNA MALAT1 Triplex Stability In Vitro.ACS Chemical Biology, vol. 17, no. 9, Sept. 2022, pp. 2437–47. Epmc, doi:10.1021/acschembio.2c00124.
Zafferani M, Martyr JG, Muralidharan D, Montalvan NI, Cai Z, Hargrove AE. Multiassay Profiling of a Focused Small Molecule Library Reveals Predictive Bidirectional Modulation of the lncRNA MALAT1 Triplex Stability In Vitro. ACS chemical biology. 2022 Sep;17(9):2437–2447.
Journal cover image

Published In

ACS chemical biology

DOI

EISSN

1554-8937

ISSN

1554-8929

Publication Date

September 2022

Volume

17

Issue

9

Start / End Page

2437 / 2447

Related Subject Headings

  • RNA, Long Noncoding
  • Organic Chemistry
  • Nucleic Acid Conformation
  • Humans
  • Gene Library
  • Diminazene
  • Calorimetry
  • 34 Chemical sciences
  • 31 Biological sciences
  • 06 Biological Sciences