Summary information and primary citation
- PDB-id
-
6xb7;
DSSR-derived features in text and
JSON formats
- Class
- RNA
- Method
- NMR
- Summary
- Ires-targeting small molecule inhibits enterovirus 71
replication via allosteric stabilization of a ternary
complex
- Reference
-
Davila-Calderon J, Patwardhan NN, Chiu LY, Sugarman A,
Cai Z, Penutmutchu SR, Li ML, Brewer G, Hargrove AE,
Tolbert BS (2020): "IRES-targeting
small molecule inhibits enterovirus 71 replication via
allosteric stabilization of a ternary complex."
Nat Commun, 11, 4775. doi:
10.1038/s41467-020-18594-3.
- Abstract
- Enterovirus 71 (EV71) poses serious threats to human
health, particularly in Southeast Asia, and no drugs or
vaccines are available. Previous work identified the stem
loop II structure of the EV71 internal ribosomal entry site
as vital to viral translation and a potential target. After
screening an RNA-biased library using a
peptide-displacement assay, we identify DMA-135 as a
dose-dependent inhibitor of viral translation and
replication with no significant toxicity in cell-based
studies. Structural, biophysical, and biochemical
characterization support an allosteric mechanism in which
DMA-135 induces a conformational change in the RNA
structure that stabilizes a ternary complex with the AUF1
protein, thus repressing translation. This mechanism is
supported by pull-down experiments in cell culture. These
detailed studies establish enterovirus RNA structures as
promising drug targets while revealing an approach and
mechanism of action that should be broadly applicable to
functional RNA targeting.
