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.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508794 | PMC |
| http://dx.doi.org/10.1038/s41467-020-18594-3 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Structural insights into how Cas9 targets nucleosomes.
Nat Commun
December 2024
Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan.
The CRISPR-associated endonuclease Cas9 derived from prokaryotes is used as a genome editing, which targets specific genomic loci by single guide RNAs (sgRNAs). The eukaryotes, the target of genome editing, store their genome DNA in chromatin, in which the nucleosome is a basic unit. Despite previous structural analyses focusing on Cas9 cleaving free DNA, structural insights into Cas9 targeting of DNA within nucleosomes are limited, leading to uncertainties in understanding how Cas9 operates in the eukaryotic genome.
View Article and Find Full Text PDFStructure-Based Design of "Head-to-Tail" Macrocyclic PROTACs.
JACS Au
December 2024
State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, No. 345 Lingling Road, Shanghai 200032, China.
Macrocyclization is a compelling strategy for conventional drug design for improving biological activity, target specificity, and metabolic stability, but it was rarely applied to the design of PROTACs possibly due to the mechanism and structural complexity. Herein, we report the rational design of the first series of "Head-to-Tail" macrocyclic PROTACs. The resulting molecule exhibited pronounced Brd4 protein degradation with low nM DC values while almost totally dismissing the "hook effect", which is a general character and common concern of a PROTAC, in multiple cancer cell lines.
View Article and Find Full Text PDFPortable Amperometric Biosensor Enhanced with Enzyme-Ternary Nanocomposites for Prostate Cancer Biomarker Detection.
Biosensors (Basel)
December 2024
Department of Cogno-Mechatronics Engineering, College of Nanoscience and Nanotechnology, Pusan National University, Busan 46241, Republic of Korea.
Enzyme-based portable amperometric biosensors are precise and low-cost medical devices used for rapid cancer biomarker screening. Sarcosine (Sar) is an ideal biomarker for prostate cancer (PCa). Because human serum and urine contain complex interfering substances that can directly oxidize at the electrode surface, rapid Sar screening biosensors are relatively challenging and have rarely been reported.
View Article and Find Full Text PDFAllosteric regulation of the tyrosine phosphatase PTP1B by a protein-protein interaction.
Protein Sci
January 2025
Department of Chemistry, Columbia University, New York, New York, USA.
The rapid identification of protein-protein interactions has been significantly enabled by mass spectrometry (MS) proteomics-based methods, including affinity purification-MS, crosslinking-MS, and proximity-labeling proteomics. While these methods can reveal networks of interacting proteins, they cannot reveal how specific protein-protein interactions alter protein function or cell signaling. For instance, when two proteins interact, there can be emergent signaling processes driven purely by the individual activities of those proteins being co-localized.
View Article and Find Full Text PDFA Copper-Binding Peptide with Therapeutic Potential against Alzheimer's Disease: From the Blood-Brain Barrier to Metal Competition.
ACS Chem Neurosci
December 2024
Department of Chemistry, Center for Research and Advanced Studies (Cinvestav), Mexico City 07360, Mexico.
Alzheimer's disease (AD) is the most common form of dementia worldwide. AD brains are characterized by the accumulation of amyloid-β peptides (Aβ) that bind Cu and have been associated with several neurotoxic mechanisms. Although the use of copper chelators to prevent the formation of Cu-Aβ complexes has been proposed as a therapeutic strategy, recent studies show that copper is an important neuromodulator that is essential for a neuroprotective mechanism mediated by Cu binding to the cellular prion protein (PrP).
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!