Publications [#369679] of Amanda Hargrove

Journal Articles

1. Davila-Calderon, J; Li, M-L; Penumutchu, SR; Haddad, C; Malcolm, L; Hargrove, AE; Brewer, G; Tolbert, BS, Enterovirus Evolution Reveals the Mechanism of an RNA-Targeted Antiviral and Determinants of Viral Replication, in Cold Spring Harbor Laboratory, vol. 10 no. 7 (February, 2023), pp. eadg3060, American Association for the Advancement of Science (AAAS) [doi]
   (last updated on 2024/12/31)

   Abstract:
   Selective pressures on viruses provide opportunities to establish target site specificity and mechanisms of antivirals. Enterovirus (EV)-A71 with resistant mutations in the stem loop (SL) II internal ribosome entry site (IRES) (SLII^resist) were selected at low doses of the antiviral dimethylamiloride (DMA)-135. The EV-A71 mutants were resistant to DMA-135 at concentrations that inhibit replication of wild-type virus. EV-A71 IRES structures harboring resistant mutations induced efficient expression of Luciferase messenger RNA in the presence of noncytotoxic doses of DMA-135. Nuclear magnetic resonance indicates that the mutations change the structure of SLII at the binding site of DMA-135 and at the surface recognized by the host protein AU-rich element/poly(U)-binding/degradation factor 1 (AUF1). Biophysical studies of complexes formed between AUF1, DMA-135, and either SLII or SLII^resist show that DMA-135 stabilizes a ternary complex with AUF1-SLII but not AUF1-SLII^resist. This work demonstrates how viral evolution elucidates the (DMA-135)-RNA binding site specificity in cells and provides insights into the viral pathways inhibited by the antiviral.