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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Patwardhan, NN; Ganser, LR; Kapral, GJ; Eubanks, CS; Lee, J; Sathyamoorthy, B; Al-Hashimi, HM; Hargrove, AE

Published Date

  • May 1, 2017

Published In

Volume / Issue

  • 8 / 5

Start / End Page

  • 1022 - 1036

PubMed ID

  • 28798862

Pubmed Central ID

  • PMC5546750

International Standard Serial Number (ISSN)

  • 2040-2503

Digital Object Identifier (DOI)

  • 10.1039/C6MD00729E


  • eng

Conference Location

  • England