Enterovirus evolution reveals the mechanism of an RNA-targeted antiviral and determinants of viral replication.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 38363831.
- Also identified by DOI 10.1126/sciadv.adg3060 and PMC identifier 10871541.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sup>resist</sup>) 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<sup>resist</sup> show that DMA-135 stabilizes a ternary complex with AUF1-SLII but not AUF1-SLII<sup>resist</sup>. 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.
Medical subject headings
- Enterovirus
- Enterovirus A, Human
- Enterovirus Infections