Recently, the mRNA platform has become the method of choice in vaccine development to find new ways to fight infectious diseases. However, this approach has shortcomings, namely that mRNA vaccines require special storage conditions, which makes them less accessible. This instability is due to the fact that the five-prime and three-prime ends of the mRNA are a substrate for the ubiquitous exoribonucleases. To address the problem, circular mRNAs have been proposed for transgene delivery as they lack these ends. Notably, circular RNAs do not have a capped five-prime end, which makes it impossible to initiate translation canonically. In this review, we summarize the current knowledge on cap-independent translation initiation methods and discuss which approaches might be most effective in developing vaccines and other biotechnological products based on circular mRNAs.
The seasonal flu vaccine is, essentially, the only known way to prevent influenza epidemics. However, this approach has limited efficacy due to the high diversity of influenza viruses. Several techniques could potentially overcome this obstacle. A recent first-in-human study of a chimeric hemagglutinin-based universal influenza virus vaccine demonstrated promising results. The coronavirus pandemic triggered the development of fundamentally new vaccine platforms that have demonstrated their effectiveness in humans. Currently, there are around a dozen messenger RNA and self-amplifying RNA flu vaccines in clinical or preclinical trials. However, the applicability of novel approaches for a universal influenza vaccine creation remains unclear. The current review aims to cover the current state of this problem and to suggest future directions for RNA-based flu vaccine development.
30 December 2019 in Fullerenes, Nanotubes and Carbon Nanostructures
Fullerene C60 is known as a promising therapeutic agent due to its antioxidant, anti-inflammatory and other properties, along with the lack of noticeable toxicity. In this article, we describe antiviral properties of aqueous fullerene C60 dispersion (ndC60) produced by biocompatible diafiltration technology and C60 amino derivatives against Herpes simplex virus type 1 (HSV-1) and Human cytomegalovirus (HCMV) infections. Their activity in vitro was evaluated by a plaque reduction assay using Vero and HF cells in pre- and post-treatment modes. Therapeutic efficacy of dnC60 and C60 derivatives was studied in DBA mice using cutaneous model of HSV-1 infection. Data obtained indicated low cytotoxicity of all used compounds for both cell lines (CC50 > 1 mg/ml). The antiviral activity of dnC60 in most tests exceeded the activity of both C60 amino adducts and acyclovir (ACV), and it demonstrated significant therapeutic effect against HSV-1 skin infection in mice.
Almost all people become infected with herpes viruses, including herpes simplex virus type 1 (HSV-1), during their lifetime. Typically, these viruses persist in a latent form that is resistant to all available antiviral medications. Under certain conditions, such as immunosuppression, the latent forms reactivate and cause disease. Moreover, strains of herpesviruses that are drug-resistant have rapidly emerged. Therefore, it is important to develop alternative methods capable of eradicating herpesvirus infections. One promising direction is the development of CRISPR/Cas systems for the therapy of herpesvirus infections. We aimed to design a CRISPR/Cas system for relatively effective long-term and safe control of HSV-1 infection. Here, we show that plasmids encoding the CRISPR/Cas9 system from Streptococcus pyogenes with a single sgRNA targeting the UL30 gene can completely suppress HSV-1 infection of the Vero cell line within 6 days and provide substantial protection within 9 days. For the first time, we show that CRISPR/CasX from Deltaproteobacteria with a single guide RNA against UL30 almost completely suppresses HSV-1 infection of the Vero cell line for 3 days and provides substantial protection for 6 days. We also found that the Cas9 protein without sgRNAs attenuates HSV-1 infection. Our results show that the developed CRISPR/Cas systems are promising therapeutic approaches to control HSV-1 infections.
1 November 2019 in Doklady Biochemistry and Biophysics
Results obtained showed that infection with HCMV prevented the death of THP-1 cells treated with DOX in both active and latent forms of infection. In the presence of mTOR inhibitors (rapamycin and Torin2), the sensitivity of the infected cells to DOX was restored. Rapamycin inhibited the expression of the HCMV protein IE1-p72 and increased sensitivity to DOX. Molecular targets for the creation of new drugs for the treatment of leukemia in patients infected with HCMV were determined.
In mammals, the binding of transcriptional activators leads to the repositioning of silent loci from the nuclear periphery to the nuclear interior. However, it remained unknown whether the same mechanism functions in Drosophila. Here, using FISH and DamID, we have shown that binding the GAL4 activator to the silent loci causes weakening of their interactions with the nuclear lamina and relocalization inside nuclei in Drosophila salivary gland cells and neurons. This mimics the removal from the nuclear periphery of a neuron-specific gene upon its activation in neurons. Salivary gland cells contain polytene chromosomes with mechanical properties, different from chromosomes of diploid cells, while neurons represent predominantly non-dividing cell type. Our results indicate a causal relationship between transcriptional activator binding and changes in the intranuclear position of loci in Drosophila. They also point to the similarity in general chromatin dynamics in mammals and Drosophila, thus strengthening the role of model organisms in studying genome architecture.