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Sci Adv ; 10(7): eadg3060, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38363831

RESUMO

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) (SLIIresist) 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 SLIIresist show that DMA-135 stabilizes a ternary complex with AUF1-SLII but not AUF1-SLIIresist. 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.


Assuntos
Enterovirus Humano A , Infecções por Enterovirus , Enterovirus , Humanos , Enterovirus/genética , Enterovirus/metabolismo , Infecções por Enterovirus/tratamento farmacológico , Infecções por Enterovirus/genética , Infecções por Enterovirus/metabolismo , Replicação Viral , Antígenos Virais , RNA Viral/metabolismo , Antivirais/farmacologia
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