Publications [#326991] of Amanda Hargrove

Journal Articles

1. 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, vol. 8 no. 5 (May, 2017), pp. 1022-1036 [doi]
   (last updated on 2024/12/31)

   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.