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Amiloride as a new RNA-binding scaffold with activity against HIV-1 TAR.

Publication ,  Journal Article
Patwardhan, NN; Ganser, LR; Kapral, GJ; Eubanks, CS; Lee, J; Sathyamoorthy, B; Al-Hashimi, HM; Hargrove, AE
Published in: Medchemcomm
May 1, 2017

Diversification of RNA-targeted scaffolds offers great promise in the search for selective ligands of therapeutically relevant RNA such as HIV-1 TAR. We herein report the establishment of amiloride as a novel RNA-binding scaffold along with synthetic routes for combinatorial C(5)- and C(6)-diversification. Iterative modifications at the C(5)- and C(6)- positions yielded derivative 24, which demonstrated a 100-fold increase in activity over the parent dimethylamiloride in peptide displacement assays. NMR chemical shift mapping was performed using the 2D SOFAST- [1H-13C] HMQC NMR method, which allowed for facile and rapid evaluation of binding modes for all library members. Cheminformatic analysis revealed distinct differences between selective and non-selective ligands. In this study, we evolved dimethylamiloride from a weak TAR ligand to one of the tightest binding selective TAR ligands reported to date through a novel combination of synthetic methods and analytical techniques. We expect these methods to allow for rapid library expansion and tuning of the amiloride scaffold for a range of RNA targets and for SOFAST NMR to allow unprecedented evaluation of small molecule:RNA interactions.

Duke Scholars

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Published In

Medchemcomm

DOI

ISSN

2040-2503

Publication Date

May 1, 2017

Volume

8

Issue

5

Start / End Page

1022 / 1036

Location

England

Related Subject Headings

  • 3405 Organic chemistry
  • 3404 Medicinal and biomolecular chemistry
  • 1115 Pharmacology and Pharmaceutical Sciences
  • 0305 Organic Chemistry
  • 0304 Medicinal and Biomolecular Chemistry
 

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Patwardhan, N. N., Ganser, L. R., Kapral, G. J., Eubanks, C. S., Lee, J., Sathyamoorthy, B., … Hargrove, A. E. (2017). Amiloride as a new RNA-binding scaffold with activity against HIV-1 TAR. Medchemcomm, 8(5), 1022–1036. https://doi.org/10.1039/C6MD00729E
Patwardhan, Neeraj N., Laura R. Ganser, Gary J. Kapral, Christopher S. Eubanks, Janghyun Lee, Bharathwaj Sathyamoorthy, Hashim M. Al-Hashimi, and Amanda E. Hargrove. “Amiloride as a new RNA-binding scaffold with activity against HIV-1 TAR.Medchemcomm 8, no. 5 (May 1, 2017): 1022–36. https://doi.org/10.1039/C6MD00729E.
Patwardhan NN, Ganser LR, Kapral GJ, Eubanks CS, Lee J, Sathyamoorthy B, et al. Amiloride as a new RNA-binding scaffold with activity against HIV-1 TAR. Medchemcomm. 2017 May 1;8(5):1022–36.
Patwardhan, Neeraj N., et al. “Amiloride as a new RNA-binding scaffold with activity against HIV-1 TAR.Medchemcomm, vol. 8, no. 5, May 2017, pp. 1022–36. Pubmed, doi:10.1039/C6MD00729E.
Patwardhan NN, Ganser LR, Kapral GJ, Eubanks CS, Lee J, Sathyamoorthy B, Al-Hashimi HM, Hargrove AE. Amiloride as a new RNA-binding scaffold with activity against HIV-1 TAR. Medchemcomm. 2017 May 1;8(5):1022–1036.
Journal cover image

Published In

Medchemcomm

DOI

ISSN

2040-2503

Publication Date

May 1, 2017

Volume

8

Issue

5

Start / End Page

1022 / 1036

Location

England

Related Subject Headings

  • 3405 Organic chemistry
  • 3404 Medicinal and biomolecular chemistry
  • 1115 Pharmacology and Pharmaceutical Sciences
  • 0305 Organic Chemistry
  • 0304 Medicinal and Biomolecular Chemistry