Jump to main content
Jump to site search

Issue 5, 2017
Previous Article Next Article

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

Author affiliations

Abstract

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.

Graphical abstract: Amiloride as a new RNA-binding scaffold with activity against HIV-1 TAR

Back to tab navigation

Supplementary files

Publication details

The article was received on 31 Dec 2016, accepted on 14 Mar 2017 and first published on 15 Mar 2017


Article type: Research Article
DOI: 10.1039/C6MD00729E
Citation: Med. Chem. Commun., 2017,8, 1022-1036
  •   Request permissions

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

    N. N. Patwardhan, L. R. Ganser, G. J. Kapral, C. S. Eubanks, J. Lee, B. Sathyamoorthy, H. M. Al-Hashimi and A. E. Hargrove, Med. Chem. Commun., 2017, 8, 1022
    DOI: 10.1039/C6MD00729E

Search articles by author

Spotlight

Advertisements