Issue 5, 2017

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

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

Supplementary files

Article information

Article type
Research Article
Submitted
31 Dec 2016
Accepted
14 Mar 2017
First published
15 Mar 2017

Med. Chem. Commun., 2017,8, 1022-1036

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

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Spotlight

Advertisements