There has been a growing interest in RNA therapeutics globally, and much progress has been made in this area, which has been further accelerated by the clinical applications of RNA-based vaccines against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Following these successful clinical trials, various technologies have been developed to improve the efficacy of RNA-based drugs. Multimerization of RNA therapeutics is one of the most attractive approaches to ensure high stability, high efficacy, and prolonged action of RNA-based drugs. In this review, we offer an overview of the representative approaches for generating repetitive functional RNAs by chemical conjugation, structural self-assembly, enzymatic elongation, and self-amplification. The therapeutic and vaccine applications of engineered multimeric RNAs in various diseases have also been summarized. By outlining the current status of multimeric RNAs, the potential of multimeric RNA as a promising treatment strategy is highlighted.
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http://dx.doi.org/10.1016/j.jconrel.2022.03.052 | DOI Listing |
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.
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December 2024
Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor-Lynen Straße 25, 81377, Munich, Germany.
Human Schlafen 11 (SLFN11) is sensitizing cells to DNA damaging agents by irreversibly blocking stalled replication forks, making it a potential predictive biomarker in chemotherapy. Furthermore, SLFN11 acts as a pattern recognition receptor for single-stranded DNA (ssDNA) and functions as an antiviral restriction factor, targeting translation in a codon-usage-dependent manner through its endoribonuclease activity. However, the regulation of the various SLFN11 functions and enzymatic activities remains enigmatic.
View Article and Find Full Text PDFViruses
November 2024
Institut de Biologie Structurale, Université Grenoble Alpes, CEA, CNRS, 38000 Grenoble, France.
The dynamic interplay between a multimeric phosphoprotein (P) and polymeric nucleoprotein (N) in complex with the viral RNA is at the heart of the functioning of the RNA-synthesizing machine of negative-sense RNA viruses of the order . P multimerization and N phosphorylation are often cited as key factors in regulating these interactions, but a detailed understanding of the molecular mechanisms is not yet available. Working with recombinant rabies virus (RABV) N and P proteins and using mainly surface plasmon resonance, we measured the binding interactions of full-length P dimers and of two monomeric fragments of either circular or linear N-RNA complexes, and we analyzed the equilibrium binding isotherms using different models.
View Article and Find Full Text PDFNat Commun
November 2024
Expression génétique microbienne, Université Paris Cité, CNRS, Institut de biologie physico-chimique, Paris, France.
Adenosine-to-inosine editing is catalyzed by adenosine deaminases acting on RNA (ADARs) in double-stranded RNA (dsRNA) regions. Although three ADARs exist in mammals, ADAR1 is responsible for the vast majority of the editing events and acts on thousands of sites in the human transcriptome. ADAR1 has been proposed to form a stable homodimer and dimerization is suggested to be important for editing activity.
View Article and Find Full Text PDFJ Mol Biol
December 2024
Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel. Electronic address:
In plants, RNA interference (RNAi) serves as a critical defense mechanism against viral infections by regulating gene expression. However, viruses have developed RNA silencing suppressor (RSS) proteins to evade this defense mechanism. The High Plains wheat mosaic virus (HPWMoV) is responsible for the High Plains disease in wheat and produces P7 and P8 proteins, which act as RNA silencing suppressors.
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