Capturing electron-driven chiral dynamics in UV-excited molecules.

Chiral molecules, used in applications such as enantioselective photocatalysis1, circularly polarized light detection2 and emission3 and molecular switches4,5, exist in two geometrical configurations that are non-superimposable mirror images of each other. These so-called (R) and (S) enantiomers exhibit different physical and chemical properties when interacting with other chiral entities. Attosecond technology might enable influence over such interactions, given that it can probe and even direct electron motion within molecules on the intrinsic electronic timescale6 and thereby control reactivity7-9. Electron currents in photoexcited chiral molecules have indeed been predicted to enable enantiosensitive molecular orientation10, but electron-driven chiral dynamics in neutral molecules have not yet been demonstrated owing to the lack of ultrashort, non-ionizing and perturbative light pulses. Here we use time-resolved photoelectron circular dichroism (TR-PECD)11-15 with an unprecedented temporal resolution of 2.9 fs to map the coherent electronic motion initiated by ultraviolet (UV) excitation of neutral chiral molecules. We find that electronic beatings between Rydberg states lead to periodic modulations of the chiroptical response on the few-femtosecond timescale, showing a sign inversion in less than 10 fs. Calculations validate this and also confirm that the combination of the photoinduced chiral current with a circularly polarized probe pulse realizes an enantioselective filter of molecular orientations following photoionization. We anticipate that our approach will enable further investigations of ultrafast electron dynamics in chiral systems and reveal a route towards enantiosensitive charge-directed reactivity.

Alteration in DNA methylation patterns: Epigenetic signatures in gastrointestinal cancers.

Abnormalities in epigenetic modifications can cause malignant transformations in cells, leading to cancers of the gastrointestinal (GI) tract, which accounts for 20% of all cancers worldwide. Among the epigenetic alterations, DNA hypomethylation is associated with genomic instability. In addition, CpG methylation and promoter hypermethylation have been recognized as biomarkers for different malignancies. In GI cancers, epigenetic alterations affect genes responsible for cell cycle control, DNA repair, apoptosis, and tumorigenic-specific signaling pathways. Understanding the pattern of alterations in DNA methylation in GI cancers could help scientists discover new molecular-based pharmaceutical treatments. This study highlights alterations in DNA methylation in GI cancers. Understanding epigenetic differences among GI cancers may improve targeted therapies and lead to the discovery of new diagnostic biomarkers.

Effects of Partial-Body, Continuous/Pulse Irradiation at Dose Rates from Flash to Conventional Rates on The Level of Surviving Blood Lymphocytes: Modeling Approach II. Two- and Multiple-Pulse Irradiation.

Mathematical models, which describe effects of partial-body, two- and multiple-pulse irradiation at high total doses D and at average dose rates N from FLASH to conventional rates on the level of surviving blood lymphocytes in humans and mice, have been developed originating in the previously proposed approach. These models predict that levels of surviving blood lymphocytes in humans and mice increase with increasing the dose rate from N = D / TR (TR is the time of the blood flowing into or out of the irradiated segment of the blood circulatory system) to FLASH rates and approach an upper limiting level equal to (1- vR), where vR is the fraction of blood volume in the irradiated segment of the blood circulatory system. Levels of surviving blood lymphocytes computed at total doses D of 10-40 Gy and at average of dose rates N, which are equal to or exceed 40 Gy/s for humans and 400 Gy/s for mice, are nearly indistinguishable from the upper limiting level. These results can be interpreted as the models reproducing the optimal blood lymphocyte sparing in these mammals after such exposures. With decreasing the dose rate from N = D/ TR to conventional rates, at multiple-pulse irradiation the levels of surviving blood lymphocytes in humans and mice decrease to lower limiting levels, whereas at two-pulse irradiation they change cyclically and do not fall below their values for the delivery time equal to TR. Additionally, effects of two- and multiple-pulse irradiation of the whole abdomen in mice on the level of surviving blood lymphocytes are simulated within the developed models. Regimens of two- and multiple-pulse irradiation are taken the same as those reported in experiments, where effects of such exposures on the level of surviving crypts in mice were studied. Juxtaposing the modeling results with the experimental data reveals that the level of surviving blood lymphocytes in mice after two- and multiple-pulse irradiation of the abdomen at average dose rates N from FLASH to conventional rates modulates the level of surviving crypts in these animals after such exposures. A hypothesis is proposed to explain this phenomenon.

Charged Amino Acid Substitutions Affect Conformation of Neuroglobin and Cytochrome c Heme Groups.

Neuroglobin (Ngb) is a cytosolic heme protein that plays an important role in protecting cells from apoptosis through interaction with oxidized cytochrome c (Cyt c) released from mitochondria. The interaction of reduced Ngb and oxidized Cyt c is accompanied by electron transfer between them and the reduction in Cyt c. Despite the growing number of studies on Ngb, the mechanism of interaction between Ngb and Cyt c is still unclear. Using Raman spectroscopy, we studied the effect of charged amino acid substitutions in Ngb and Cyt c on the conformation of their hemes. It has been shown that Ngb mutants E60K, K67E, K95E and E60K/E87K demonstrate changed heme conformations with the lower probability of the heme planar conformation compared to wild-type Ngb. Moreover, oxidized Cyt c mutants K25E, K72E and K25E/K72E demonstrate the decrease in the probability of methyl-radicals vibrations, indicating the higher rigidity of the protein microenvironment. It is possible that these changes can affect electron transfer between Ngb and Cyt c.

Valleytronics in bulk MoS2 with a topologic optical field.

The valley degree of freedom1-4 of electrons in materials promises routes towards energy-efficient information storage with enticing prospects for quantum information processing5-7. Current challenges in utilizing valley polarization are symmetry conditions that require monolayer structures8,9 or specific material engineering10-13, non-resonant optical control to avoid energy dissipation and the ability to switch valley polarization at optical speed. We demonstrate all-optical and non-resonant control over valley polarization using bulk MoS2, a centrosymmetric material without Berry curvature at the valleys. Our universal method utilizes spin angular momentum-shaped trefoil optical control pulses14,15 to switch the material's electronic topology and induce valley polarization by transiently breaking time and space inversion symmetry16 through a simple phase rotation. We confirm valley polarization through the transient generation of the second harmonic of a non-collinear optical probe pulse, depending on the trefoil phase rotation. The investigation shows that direct optical control over the valley degree of freedom is not limited to monolayer structures. Indeed, such control is possible for systems with an arbitrary number of layers and for bulk materials. Non-resonant valley control is universal and, at optical speeds, unlocks the possibility of engineering efficient multimaterial valleytronic devices operating on quantum coherent timescales.

Effects of Partial-Body, Continuous/Pulse Irradiation at Dose Rates from Flash to Conventional Rates on the Level of Surviving Blood Lymphocytes: Modeling Approach. I. Continuous Irradiation.

A mathematical model developed by Cucinotta and Smirnova is extended to describe effects of continuous, partial-body irradiation at high doses D and at dose N rates from FLASH to conventional rates on the level of surviving blood lymphocytes in humans and small laboratory animals (mice). Specifically, whereas the applicability of the model is limited to the exposure times shorter than a single cardiac cycle T0, the extended model is capable of describing such effects for the aforementioned and longer exposure times. The extended model is implemented as the algebraic equations. It predicts that the level of surviving blood lymphocytes in humans and mice increases with increasing the dose rate from N = D / T0 to FLASH rates and approaches the upper limiting level of 1 - v R where v R is the fraction of blood volume in the irradiated part of the blood circulatory system. Levels of surviving blood lymphocytes computed at doses from 10 Gy to 40 Gy and at dose rates N, which equal or exceed 40 Gy/s for humans and 400 Gy/s for mice, are nearly indistinguishable from the upper limiting level. In turn, the level of surviving blood lymphocytes in humans and mice decreases with decreasing the dose rate from N = D / T0 to conventional rates and approaches a lower limiting level. This level strongly depends on the dose D (it is smaller at larger values of D) with a slight dependence on the dose rate N. The model with the parameters specified for mice (together with the model of the dynamics of lymphopoietic system in mice after partial-body irradiation) reproduce, on a quantitative level, the experimental data, according to which the concentration of blood lymphocytes measured in mice in one day after continuous, partial-body irradiation at a high dose and conventional dose rate is smaller at the larger value of vR. Additionally, the model predicts at the same high dose (>10 Gy) a faster restoration of the blood lymphocyte population in humans exposed to continuous, partial-body irradiation at a FLASH dose rate compared to a conventional dose rate.

Advanced Therapeutic Medicinal Products in Bone and Cartilage Defects.

The number of patients with functional loss of bone and cartilage tissue has shown an increasing trend. Insufficient or inappropriate conventional treatments applied for trauma, orthopedic diseases, or other bone and cartilage-related disorders can lead to bone and cartilage damage. This represents a worldwide public health issue and a significant economic burden. Advanced therapeutic medicinal products (ATMPs) proposed promising alternative therapeutic modalities by application of cell-based and tissue engineering approaches. Recently, several ATMPs have been developed to promote bone and cartilage tissue regeneration. Fifteen ATMPs, two related to bone and 13 related to cartilage, have received regulatory approval and marketing authorization. However, four ATMPs were withdrawn from the market for various reasons. However, ATMPs that are still on the market have demonstrated positive results, their broad application faced limitations. The development and standardization of methodologies will be a major challenge in the coming decades. Currently, the number of ATMPs in clinical trials using mesenchymal stromal cells or chondrocytes indicates a growing recognition that current ATMPs can be improved. Research on bone and cartilage tissue regeneration continues to expand. Cell-based therapies are likely to be clinically supported by the new ATMPs, innovative fabrication processes, and enhanced surgical approaches. In this study, we highlighted the available ATMPs that have been used in bone and cartilage defects and discussed their advantages and disadvantages in clinical applications.

Four sides to the story: A proteomic comparison of liquid-phase and matrix-bound extracellular vesicles in 2D and 3D cell cultures.

Multipotent mesenchymal stromal cells (MSCs)-derived extracellular vesicles (EVs) play important roles in cellular communication and are extensively studied as promising therapeutic agents. While there is a substantial pool of studies on liquid-phase EVs, data on EVs bound to the extracellular matrix (ECM) is lacking. There is also an emerging trend of accumulating and comparing data on characteristics of EVs obtained in different culturing conditions. Aiming to reveal proteomic signatures of EVs obtained from conditioned media and ECM of MSCs cultured in 2D and 3D conditions, we performed liquid chromatography with tandem mass spectrometry. Bioinformatic analysis revealed common patterns in proteomic composition of liquid-phase EVs and matrix-bound vesicles (MBVs), namely extracellular environment organization, immune, and transport pathways enrichment. However, extracellular environmental organization pathways are more enriched in liquid-phase EVs than in MBVs, while MBVs proteins noticeably enrich enzymatic pathways. Furthermore, each type of EVs from 2D and 3D cultures has a unique differential abundance profile. We have also performed comparative functional assays, namely scratch assay to assess EVs effect on cell migration and tubulogenesis assay to evaluate EVs angiogenic potential. We found that both liquid-phase EVs and MBVs enhance cell migration, while angiogenic potential is higher in MBVs. Results of the present study suggest that while both liquid-phase EVs and MBVs have therapeutic potential, some unique features of each subgroup may determine optimal areas of their application.

Observation of interband Berry phase in laser-driven crystals.

Ever since its discovery1, the notion of the Berry phase has permeated all branches of physics and plays an important part in a variety of quantum phenomena2. However, so far all its realizations have been based on a continuous evolution of the quantum state, following a cyclic path. Here we introduce and demonstrate a conceptually new manifestation of the Berry phase in light-driven crystals, in which the electronic wavefunction accumulates a geometric phase during a discrete evolution between different bands, while preserving the coherence of the process. We experimentally reveal this phase by using a strong laser field to engineer an internal interferometer, induced during less than one cycle of the driving field, which maps the phase onto the emission of higher-order harmonics. Our work provides an opportunity for the study of geometric phases, leading to a variety of observations in light-driven topological phenomena and attosecond solid-state physics.

Effects of Progesterone and Selective Ligands of Membrane Progesterone Receptors in HepG2 Cells of Human Hepatocellular Carcinoma.

Progesterone exerts multiple effects in different tissues through nuclear receptors (nPRs) and through membrane receptors (mPRs) of adiponectin and progestin receptor families. The effect of progesterone on the cells through different types of receptors can vary significantly. At the same time, it affects the processes of proliferation and apoptosis in normal and tumor tissues in a dual way, stimulating proliferation and carcinogenesis in some tissues, suppressing them and stimulating cell death in others. In this study, we have shown the presence of high level of mPRß mRNA and protein in the HepG2 cells of human hepatocellular carcinoma. Expression of other membrane and classical nuclear receptors was not detected. It could imply that mPRß has an important function in the HepG2 cells. The main goal of the work was to study functions of this protein and mechanisms of its action in human hepatocellular carcinoma cells. Previously, we have identified selective mPRs ligands, compounds LS-01 and LS-02, which do not interact with nuclear receptors. Their employment allows differentiating the effects of progestins mediated by different types of receptors. Effects of progesterone, LS-01, and LS-02 on proliferation and death of HepG2 cells were studied in this work, as well as activating phosphorylation of two kinases, p38 MAPK and JNK, under the action of three steroids. It was shown that all three progestins after 72 h of incubation with the cells suppressed their viability and stimulated appearance of phosphatidylserine on the outer surface of the membranes, which was detected by binding of annexin V, but they did not affect DNA fragmentation of the cell nuclei. Progesterone significantly reduced expression of the proliferation marker genes and stimulated expression of the p21 protein gene, but had a suppressive effect on the expression of some proapoptotic factor genes. All three steroids activated JNK in these cells, but had no effect on the p38 MAPK activity. The effects of progesterone and selective mPRs ligands in HepG2 cells were the same in terms of suppression of proliferation and stimulation of apoptotic changes in outer membranes, therefore, they were mediated through interaction with mPRß. JNK is a member of the signaling cascade activated in these cells by the studied steroids.

Electrophoretically Co-Deposited Collagen-Lactoferrin Membranes with Enhanced Pro-Regenerative Properties for Oral Soft Tissue Regeneration.

The quality of soft tissue defect regeneration after dental surgeries largely determines their final success. Collagen membranes have been proposed for the healing of such defects, but in some cases, they do not guarantee a sufficient volume of the regenerated tissue and vascularization. For this purpose, lactoferrin, a protein with natural pro-regenerative, anti-inflammatory, and pro-angiogenic activity, can be added to collagen. In this article, we used a semipermeable barrier-assisted electrophoretic deposition (SBA-EPD) method for the production of collagen-lactoferrin membranes. The membrane structure was studied by SEM, and its mechanical properties were shown. The lactoferrin release kinetics were shown by ELISA within 75 h. When tested in vitro, we demonstrated that the collagen-lactoferrin membranes significantly increased the proliferation of keratinocytes (HaCaT) and fibroblasts (977hTERT) compared to blank collagen membranes. In vivo, on the vestibuloplasty and free gingival graft harvesting models, we showed that collagen-lactoferrin membranes decreased the wound inflammation and increased the healing rates and regeneration quality. In some parameters, collagen-lactoferrin membranes outperformed not only blank collagen membranes, but also the commercial membrane Mucograft®. Thus, we proved that collagen-lactoferrin membranes produced by the SBA-EPD method may be a valuable alternative to commercially used membranes for soft tissue regeneration in the oral cavity.

Optical Alignment and Optical Orientation of Excitons in CdSe/CdS Colloidal Nanoplatelets.

Optical alignment and optical orientation of excitons are studied experimentally on an ensemble of core/shell CdSe/CdS colloidal nanoplatelets. Linear and circular polarization of photoluminescence during resonant excitation of excitons is measured at cryogenic temperatures and with magnetic fields applied in the Faraday geometry. The developed theory addresses the optical alignment and optical orientation of excitons in colloidal nanocrystals, taking into account both bright and dark exciton states in the presence of strong electron-hole exchange interaction and the random in-plane orientation of nanoplatelets within the ensemble. Our theoretical analysis of the obtained experimental data allows us to evaluate the exciton fine structure parameters, the g-factors, and the spin lifetimes of the bright and dark excitons. The optical alignment effect enables the identification of the exciton and trion contributions to the emission spectrum, even in the absence of their clear separation in the spectra.

Ultrafast control over chiral sum-frequency generation.

We introduce an ultrafast all-optical approach for efficient chiral recognition that relies on the interference between two low-order nonlinear processes that are ubiquitous in nonlinear optics: sum-frequency generation and third-harmonic generation. In contrast to traditional sum-frequency generation, our approach encodes the medium's handedness in the intensity of the emitted harmonic signal, rather than in its phase, and it enables full control over the enantiosensitive response. We show how, by sculpting the sub-optical-cycle oscillations of the driving laser field, we can force one molecular enantiomer to emit bright light while its mirror twin remains dark, thus reaching the ultimate efficiency limit of chiral sensitivity via low-order nonlinear light-matter interactions. Our work paves the way for ultrafast and highly efficient imaging and control of the chiral electronic clouds of chiral molecules using lasers with moderate intensities, in all states of matter: from gases to liquids to solids, with molecular specificity and on ultrafast time scales.

Correlation between the Chemiluminescent Activity of Neutrophilic Granulocytes and the Lipid Peroxidation-Antioxidant Defense System in Gastric Cancer Associated with Helicobacter pylori Infection.

AIM: To study the processes of lipid peroxidation and the activity of antioxidant defense enzymes depending on the chemiluminescent activity of neutrophilic granulocytes in patients with gastric cancer associated with H. pylori infection, depending on the stage. MATERIALS AND METHODS: A total of 39 patients with stage I-II gastric cancer and 30 patients with stage III-IV gastric cancer were examined. A study of the chemiluminescent activity of neutrophilic granulocytes was carried out and the parameters of the lipid peroxidation system and antioxidant protection in plasma were determined using the spectrophotometric method. Statistical data processing was performed using the Statistica 7.0 software package (StatSoft, St Tulsa, OK, USA). RESULTS: In patients with gastric cancer associated with H. pylori infection, regardless of stage, the proportion of neutrophilic granulocytes with normal activity did not exceed 1/3 of the total number of patients, and the remaining 2/3 of patients had altered chemiluminescent activity of neutrophilic granulocytes. In patients with gastric cancer, by I-II stage of the disease, the majority revealed a reduced function of neutrophilic granulocytes, and in patients with gastric cancer in stage III-IV of the disease, the majority showed increased chemiluminescent activity of neutrophilic granulocytes. CONCLUSIONS: In all patients with gastric cancer associated with H. pylori infection, regardless of the stage of the disease, an increase in lipid peroxidation processes with activation of antioxidant defense enzymes was detected. At the same time, there were no statistically significant differences between the indicators of the system lipid peroxidation-antioxidant protection depending on the stage of gastric cancer and the chemiluminescent activity of neutrophilic granulocytes, which likely indicates that all reactive oxygen species produced by neutrophilic granulocytes in the respiratory burst are consumed locally, minimally affecting the development of oxidative stress in the blood plasma.

NOVAprep-miR-Cervix: New Method for Evaluation of Cervical Dysplasia Severity Based on Analysis of Six miRNAs.

Cervical cancer is one of the most common gynecological malignancies and it is preventable through the yearly diagnosis and management of pre-cancerous cervical disease. The profile of miRNA expression in cervical epithelium cells is altered with cervical dysplasia development and further progression. The NOVAprep-miR-CERVIX is a new approach for the assessment of cervical dysplasia through the analysis of six marker miRNAs. This study aims to evaluate theperformance and diagnostic potency of the new method. Cytological smears from 226 women (NILM, n.114; HSIL, n.112) were included in the study. A VPH test was performed with RealBest DNAHPV HR screen Kit, six marker miRNAs (miR-21, -29b, -145, -451a, -1246, -1290) were assayed using NOVAprep-miR-CERVIX kit. Obtained data were analyzed using the Delta Ct method and random forest machine learning algorithm. The results of the quantitative analysis of six microRNAs were expressed as a miR-CERVIX parameter, which ranged from 0 to 1, where "0" corresponded to the healthy cervical epithelium, while "1" corresponded to high-grade squamous intraepithelial dysplasia. The average value of miR-CERVIX differed in groups of NILM and HSIL samples (0.34 vs. 0.72; p < 0.000005). An estimation of miR-CERVIX allowed for the differentiation between healthy and pre-cancerous samples with sensitivity of 0.79 and specificity of 0.79, as well as to confirm HSIL with specificity of 0.98. Interestingly, the HSIL group included HPV(+) and HPV(-) samples, which were statistically significantly different in terms of miR-CERVIX value. Analysis of CC-associated miRNAs in material of cervical smear might serve as an additional method for the evaluation of cervical dysplasia severity.

Intramolecular Hydrogen Bonding in N6-Substituted 2-Chloroadenosines: Evidence from NMR Spectroscopy.

Two forms were found in the NMR spectra of N6-substituted 2-chloroadenosines. The proportion of the mini-form was 11-32% of the main form. It was characterized by a separate set of signals in COSY, 15N-HMBC and other NMR spectra. We assumed that the mini-form arises due to the formation of an intramolecular hydrogen bond between the N7 atom of purine and the N6-CH proton of the substituent. The 1H,15N-HMBC spectrum confirmed the presence of a hydrogen bond in the mini-form of the nucleoside and its absence in the main form. Compounds incapable of forming such a hydrogen bond were synthesized. In these compounds, either the N7 atom of the purine or the N6-CH proton of the substituent was absent. The mini-form was not found in the NMR spectra of these nucleosides, confirming the importance of the intramolecular hydrogen bond in its formation.

C-Methylated Spermidine Derivatives: Convenient Syntheses and Antizyme-Related Effects.

The biogenic polyamines, spermidine (Spd) and spermine (Spm), are present at millimolar concentrations in all eukaryotic cells, where they participate in the regulation of vitally important cellular functions. Polyamine analogs and derivatives are a traditional and important instrument for the investigation of the cellular functions of polyamines, enzymes of their metabolism, and the regulation of the biosynthesis of antizyme-a key downregulator of polyamine homeostasis. Here, we describe convenient gram-scale syntheses of a set of C-methylated analogs of Spd. The biochemical properties of these compounds and the possibility for the regulation of their activity by moving a methyl group along the polyamine backbone and by changing the stereochemistry of the chiral center(s) are discussed.

Hepatitis Delta Virus Antigens Trigger Oxidative Stress, Activate Antioxidant Nrf2/ARE Pathway, and Induce Unfolded Protein Response.

Hepatitis delta virus (HDV) is a viroid-like satellite that may co-infect individuals together with hepatitis B virus (HBV), as well as cause superinfection by infecting patients with chronic hepatitis B (CHB). Being a defective virus, HDV requires HBV structural proteins for virion production. Although the virus encodes just two forms of its single antigen, it enhances the progression of liver disease to cirrhosis in CHB patients and increases the incidence of hepatocellular carcinoma. HDV pathogenesis so far has been attributed to virus-induced humoral and cellular immune responses, while other factors have been neglected. Here, we evaluated the impact of the virus on the redox status of hepatocytes, as oxidative stress is believed to contribute to the pathogenesis of various viruses, including HBV and hepatitis C virus (HCV). We show that the overexpression of large HDV antigen (L-HDAg) or autonomous replication of the viral genome in cells leads to increased production of reactive oxygen species (ROS). It also leads to the upregulated expression of NADPH oxidases 1 and 4, cytochrome P450 2E1, and ER oxidoreductin 1α, which have previously been shown to mediate oxidative stress induced by HCV. Both HDV antigens also activated the Nrf2/ARE pathway, which controls the expression of a spectrum of antioxidant enzymes. Finally, HDV and its large antigen also induced endoplasmic reticulum (ER) stress and the concomitant unfolded protein response (UPR). In conclusion, HDV may enhance oxidative and ER stress induced by HBV, thus aggravating HBV-associated pathologies, including inflammation, liver fibrosis, and the development of cirrhosis and hepatocellular carcinoma.

SARS-CoV-2 Establishes a Productive Infection in Hepatoma and Glioblastoma Multiforme Cell Lines.

Severe acute respiratory syndrome associated coronavirus 2 (SARS-CoV-2) emerged at the end of 2019 and rapidly caused a pandemic that led to the death of >6 million people due to hypercoagulation and cytokine storm. In addition, SARS-CoV-2 triggers a wide array of pathologies, including liver dysfunction and neurological disorders. It remains unclear if these events are due to direct infection of the respective tissues or result from systemic inflammation. Here, we explored the possible infection of hepatic and CNS cell lines by SARS-CoV-2. We show that even moderate expression levels of the angiotensin-converting enzyme 2 (ACE2) are sufficient for productive infection. SARS-CoV-2 infects hepatoma Huh7.5 and HepG2 cells but not non-transformed liver progenitor or hepatocyte/cholangiocyte-like HepaRG cells. However, exposure to the virus causes partial dedifferentiation of HepaRG cells. SARS-CoV-2 can also establish efficient replication in some low-passage, high-grade glioblastoma cell lines. In contrast, embryonal primary astrocytes or neuroblastoma cells did not support replication of the virus. Glioblastoma cell permissiveness is associated with defects in interferon production. Overall, these results suggest that liver dysfunction during COVID-19 is not due to infection of these tissues by SARS-CoV-2. Furthermore, tumors may potentially serve as reservoirs for the virus during infection.

Nucleoside Analogs That Inhibit SARS-CoV-2 Replication by Blocking Interaction of Virus Polymerase with RNA.

The SARS-CoV-2 betacoronavirus pandemic has claimed more than 6.5 million lives and, despite the development and use of COVID-19 vaccines, remains a major global public health problem. The development of specific drugs for the treatment of this disease remains a very urgent task. In the context of a repurposing strategy, we previously screened a library of nucleoside analogs showing different types of biological activity against the SARS-CoV-2 virus. The screening revealed compounds capable of inhibiting the reproduction of SARS-CoV-2 with EC50 values in the range of 20-50 µM. Here we present the design and synthesis of various analogs of the leader compounds, the evaluation of their cytotoxicity and antiviral activity against SARS-CoV-2 in cell cultures, as well as experimental data on RNA-dependent RNA polymerase inhibition. Several compounds have been shown to prevent the interaction between the SARS-CoV-2 RNA-dependent RNA polymerase and the RNA substrate, likely inhibiting virus replication. Three of the synthesized compounds have also been shown to inhibit influenza virus. The structures of these compounds can be used for further optimization in order to develop an antiviral drug.