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Regulation of MALAT1 triple helix stability and in vitro degradation by diphenylfurans.

Publication ,  Journal Article
Donlic, A; Zafferani, M; Padroni, G; Puri, M; Hargrove, AE
Published in: Nucleic acids research
August 2020

Small molecule-based modulation of a triple helix in the long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been proposed as an attractive avenue for cancer treatment and a model system for understanding small molecule:RNA recognition. To elucidate fundamental recognition principles and structure-function relationships, we designed and synthesized nine novel analogs of a diphenylfuran-based small molecule DPFp8, a previously identified lead binder of MALAT1. We investigated the role of recognition modalities in binding and in silico studies along with the relationship between affinity, stability and in vitro enzymatic degradation of the triple helix. Specifically, molecular docking studies identified patterns driving affinity and selectivity, including limited ligand flexibility, as observed by ligand preorganization and 3D shape complementarity for the binding pocket. The use of differential scanning fluorimetry allowed rapid evaluation of ligand-induced thermal stabilization of the triple helix, which correlated with decreased in vitro degradation of this structure by the RNase R exonuclease. The magnitude of stabilization was related to binding mode and selectivity between the triple helix and its precursor stem loop structure. Together, this work demonstrates the value of scaffold-based libraries in revealing recognition principles and of raising broadly applicable strategies, including functional assays, for small molecule-RNA targeting.

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Published In

Nucleic acids research

DOI

EISSN

1362-4962

ISSN

0305-1048

Publication Date

August 2020

Volume

48

Issue

14

Start / End Page

7653 / 7664

Related Subject Headings

  • RNA, Long Noncoding
  • RNA Stability
  • Nucleic Acid Conformation
  • Molecular Docking Simulation
  • Ligands
  • Furans
  • Exoribonucleases
  • Developmental Biology
  • 41 Environmental sciences
  • 34 Chemical sciences
 

Citation

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Donlic, A., Zafferani, M., Padroni, G., Puri, M., & Hargrove, A. E. (2020). Regulation of MALAT1 triple helix stability and in vitro degradation by diphenylfurans. Nucleic Acids Research, 48(14), 7653–7664. https://doi.org/10.1093/nar/gkaa585
Donlic, Anita, Martina Zafferani, Giacomo Padroni, Malavika Puri, and Amanda E. Hargrove. “Regulation of MALAT1 triple helix stability and in vitro degradation by diphenylfurans.Nucleic Acids Research 48, no. 14 (August 2020): 7653–64. https://doi.org/10.1093/nar/gkaa585.
Donlic A, Zafferani M, Padroni G, Puri M, Hargrove AE. Regulation of MALAT1 triple helix stability and in vitro degradation by diphenylfurans. Nucleic acids research. 2020 Aug;48(14):7653–64.
Donlic, Anita, et al. “Regulation of MALAT1 triple helix stability and in vitro degradation by diphenylfurans.Nucleic Acids Research, vol. 48, no. 14, Aug. 2020, pp. 7653–64. Epmc, doi:10.1093/nar/gkaa585.
Donlic A, Zafferani M, Padroni G, Puri M, Hargrove AE. Regulation of MALAT1 triple helix stability and in vitro degradation by diphenylfurans. Nucleic acids research. 2020 Aug;48(14):7653–7664.
Journal cover image

Published In

Nucleic acids research

DOI

EISSN

1362-4962

ISSN

0305-1048

Publication Date

August 2020

Volume

48

Issue

14

Start / End Page

7653 / 7664

Related Subject Headings

  • RNA, Long Noncoding
  • RNA Stability
  • Nucleic Acid Conformation
  • Molecular Docking Simulation
  • Ligands
  • Furans
  • Exoribonucleases
  • Developmental Biology
  • 41 Environmental sciences
  • 34 Chemical sciences