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

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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

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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, Advance Article
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    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, Advance Article , DOI: 10.1039/C6MD00729E

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