We describe the development of a new type of scaffold to target RNA structures. Multivalent binding oligomers (MBOs) are molecules in which multiple sidechains extend from a polyamine backbone such that favorable RNA binding occurs. We have used this strategy to develop MBO-based inhibitors to prevent the association of a protein-RNA complex, Tat-TAR, that is essential for HIV replication. In vitro binding assays combined with model cell-based assays demonstrate that the optimal MBOs inhibit Tat-TAR binding at low micromolar concentrations. Antiviral studies are also consistent with the in vitro and cell-based assays. MBOs provide a framework for the development of future RNA-targeting molecules.
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http://dx.doi.org/10.1016/j.bmcl.2009.10.078 | DOI Listing |
Nat Struct Mol Biol
January 2025
Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA.
The epigenetic cofactor ENL (eleven-nineteen-leukemia) and the acetyltransferase MOZ (monocytic leukemia zinc finger) have vital roles in transcriptional regulation and are implicated in aggressive forms of leukemia. Here, we describe the mechanistic basis for the intertwined association of ENL and MOZ. Genomic analysis shows that ENL and MOZ co-occupy active promoters and that MOZ recruits ENL to its gene targets.
View Article and Find Full Text PDFMol Biol Cell
January 2025
Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
SPOP is a Cul3 substrate adaptor responsible for the degradation of many proteins related to cell growth and proliferation. Because mutation or misregulation of SPOP drives cancer progression, understanding the suite of SPOP substrates is important to understanding the regulation of cell proliferation. Here, we identify Nup153, a component of the nuclear basket of the nuclear pore complex, as a novel substrate of SPOP.
View Article and Find Full Text PDFJ Phys Chem Lett
January 2025
School of Physics and Electronics, Shandong Normal University, Jinan 250014, China.
Addressing the frequent emergence of SARS-CoV-2 mutant strains requires therapeutic approaches with innovative neutralization mechanisms. The targeting of multivalent nanobodies can enhance potency and reduce the risk of viral escape, positioning them as promising drug candidates. Here, the synergistic mechanisms of the two types of nanobodies are investigated deeply.
View Article and Find Full Text PDFSmall
January 2025
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
Capturing circulating tumor cells (CTCs) in vivo from the bloodstream lessens tumor metastasis and recurrence risks. However, the absence of CTC receptors due to epithelial-mesenchymal transition (EMT), the limited binding capacity of a single ligand, and the complexity of the blood flow environment significantly reduce the efficiency of CTC capture in vivo. Herein, a multivalent ligand-decorated microsphere enrichment system (MLMES) is crafted that incorporates a capture column replete with an immunosorbent that precisely recognizes and binds the stably expressed cluster of differentiation 44 (CD44) and glucose transporter protein 1 (GLUT1) receptors present on the exterior of CTCs.
View Article and Find Full Text PDFCancers (Basel)
December 2024
Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
: Fibroblast activation protein (FAP)-targeted theranostic radiopharmaceuticals have shown desired tumor-to-background organ selectivity due to the ubiquitous presence of FAP within the tumor microenvironment. However, suboptimal tumor retention and fast clearance have hindered their use to deliver effective cancer therapies. With well-documented FAP-targeting moieties and linkers appending them to optimal chelators, the development of copper radiopharmaceuticals has attracted considerable interest, given the fact that an ideal theranostic pair of copper radionuclides (Cu: t = 12.
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