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) 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 show that DMA-135 stabilizes a ternary complex with AUF1-SLII but not AUF1-SLII. 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.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10871541 | PMC |
| http://dx.doi.org/10.1126/sciadv.adg3060 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Attention-guided convolutional network for bias-mitigated and interpretable oral lesion classification.
Sci Rep
December 2024
Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, Canada.
Accurate diagnosis of oral lesions, early indicators of oral cancer, is a complex clinical challenge. Recent advances in deep learning have demonstrated potential in supporting clinical decisions. This paper introduces a deep learning model for classifying oral lesions, focusing on accuracy, interpretability, and reducing dataset bias.
View Article and Find Full Text PDFSleep drive is coupled to tissue damage via shedding of Caenorhabditis elegans EGFR ligand SISS-1.
Nat Commun
December 2024
Department of Biology, California State University Northridge, Northridge, CA, USA.
The benefits of sleep extend beyond the nervous system. Peripheral tissues impact sleep regulation, and increased sleep is observed in response to damaging conditions, even those that selectively affect non-neuronal cells. However, the 'sleep need' signal released by stressed tissues is not known.
View Article and Find Full Text PDFColon-targeted engineered postbiotics nanoparticles alleviate osteoporosis through the gut-bone axis.
Nat Commun
December 2024
Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, China.
The potential for mitigating intestinal inflammation through the gut-bone axis in the treatment of osteoporosis is significant. While various gut-derived postbiotics or bacterial metabolites have been created as dietary supplements to prevent or reverse bone loss, their efficacy and safety still need improvement. Herein, a colon-targeted drug delivery system is developed using surface engineering of polyvinyl butyrate nanoparticles by shellac resin to achieve sustained release of postbiotics butyric acid at the colorectal site.
View Article and Find Full Text PDFFunctional anatomy of zinc finger antiviral protein complexes.
Nat Commun
December 2024
Laboratory of Retrovirology, The Rockefeller University, New York, NY, 10065, USA.
ZAP is an antiviral protein that binds to and depletes viral RNA, which is often distinguished from vertebrate host RNA by its elevated CpG content. Two ZAP cofactors, TRIM25 and KHNYN, have activities that are poorly understood. Here, we show that functional interactions between ZAP, TRIM25 and KHNYN involve multiple domains of each protein, and that the ability of TRIM25 to multimerize via its RING domain augments ZAP activity and specificity.
View Article and Find Full Text PDFSite-specific seeding of Lewy pathology induces distinct pre-motor cellular and dendritic vulnerabilities in the cortex.
Nat Commun
December 2024
Weldon School of Biomedical Engineering, West Lafayette, Indiana, IN, USA.
Circuit-based biomarkers distinguishing the gradual progression of Lewy pathology across synucleinopathies remain unknown. Here, we show that seeding of α-synuclein preformed fibrils in mouse dorsal striatum and motor cortex leads to distinct prodromal-phase cortical dysfunction across months. Our findings reveal that while both seeding sites had increased cortical pathology and hyperexcitability, distinct differences in electrophysiological and cellular ensemble patterns were crucial in distinguishing pathology spread between the two seeding sites.
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!