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AbstractThe results of an electron microscopic study of the effect of heteropoly acids (HPAs) with a Keggin structure on particles of influenza A/Aichi/1/68 (H3N2) and A/California/07/09 (H1N1) pdm09 viruses are presented. It is shown that the action of HPAs on viral particles leads to a complete (or partial) removal of transmembrane glycoproteins and the destruction of matrix protein M1, which manifests itself in the deformations and destruction of viral membranes. Using the A/California/07/09 (H1N1) pdm09 viruses as an example, it is shown that the efficiency of the destruction of the viral envelope by HPAs depends on the medium in which the viruses are cultured. The mechanism of destruction is proposed, which involves the extraction of cholesterol, etching of phospholipids, and the formation of pores in the lipid membrane as a result of the action of heteropolyanions. It is assumed that the penetration of protons through the formed pores can lead to the destruction of the matrix protein M1.

Fifty-four strains of H5N1 highly pathogenic avian influenza (HPAI) virus were isolated from wild birds in the ecosystems of northern Eurasia and from poultry in the south of western Siberia (July 2005), at the mouth of Volga River (November 2005), at Uvs-Nur Lake on the boundary of the Great Lakes Depression in western Mongolia and the Tyva Republic of Russia (June 2006), in the vicinity of Moscow (February 2007), in the southeastern part of the Russian Plain (September 2007 and December 2007), and in the far east (April 2008) of the Russian Federation and were phenotypically characterized and deposited into the Russian state collection of viruses. Complete genome nucleotide sequences for 24 strains were obtained and deposited into GenBank. In all cases when strains were isolated from both wild birds and poultry in the same outbreak these strains were genetically closely related to each other. Until 2008 all HPAI H5N1 strains isolated in northern Eurasia clustered genetically with the viruses from Kukunor Lake (Qinghai Province, China), known as genotype 2.2 or the “Qinghai-Siberian” genotype. The viruses from the Qinghai-Siberian genotype have continued to evolve from those initially introduced into western Siberia in 2005 into two genetic groups: “Iran–North Caucasian” and “Tyva-Siberian.” In vitro replication potential (50% tissue-culture infectious dose in porcine embryo kidney) of Qinghai-Siberian strains decreased over time, which could reflect decreasing virulence. Comparison of genome sequences with biological characteristics of the respective strains permitted us to identify point mutations in PB2, PB1, PA, HA, NP, NA, M2, NS1, and NS2 that possibly influenced the level of replication potential. The HPAI H5N1 virus, which penetrated into the south of the Russian Far East in spring 2008, belonged to genotype 2.3.2.

— The need for new effective compounds that can serve as prototype drugs for the treatment of viral infections and various types of cancer has not diminished over the past decades. This is due to the emergence of new pathogens and the development of resistance to existing drugs. Nucleoside analogues are one of the most common classes of drugs that have long served as the basis for antiviral and anticancer therapies. The analogues' similarity to natural nucleosides, which are involved in many biological processes, allows them to inhibit key enzymes in the development of pathogenic processes. The antiviral properties of synthetic nucleosides and their analogues are of great interest in connection with the primary or re-emerging viruses with epidemic and/or pandemic potential, such as Ebola, Zika, Middle East respiratory syndrome (MERS-CoV), severe acute respiratory syndrome viruses, coronaviruses 1 and 2 (SARS and SARS-CoV-2), or new strains of influenza. The aim of our work was to create new uracil derivatives—acyclic reverse fleximers as potential antiviral and antitumor agents. The substances were obtained by the Suzuki–Miyaura reaction and characterized using modern physicochemical methods. Antiviral activity against influenza A/California/7/2009 and SARS-CoV-2 was tested, and cytotoxicity was assessed on leukemia and neuroblastoma cell cultures.

A comparative study of the hemagglutinin (HA) receptor binding site (RBS) of a number of H13 influenza viruses isolated from Laridae family of birds (gulls) and other influenza viruses obtained from the Anatidae family (ducks) was conducted. The affinity of all viruses to alpha N-acetylneuraminic acid (Neu5Acα), 3′sialyllactose (3′SL), and sialylglycopolymers bearing 3′-sialyl(N-acetyllactosamine) (3′SLN-PAA), [Neu5Acα(2-3)Galβ(1-4)][-Fucα(1-3)]GlcNAcβ (SLex-PAA), and [Neu5Acα(2-3)Galβ(1-3)][-Fucα(1-4)]GlcNAcβ (SLea-PAA), was determined. The last three polymer glycoconjugates were synthesized for determining the contribution of carbohydrate chains after the galactose link to the binding with the receptor. The difference in affinity between 3′SL and Neu5Acα in all studied H13 viruses is small, which indicates a less significant role of the galactose moiety in the binding to the receptor. The results of virus binding with polymer sialylglycoconjugates indicates that the method of linking, the third monosaccharide moiety, and the presence of an extra fucose substitute in this moiety may influence the binding considerably. For viruses isolated from ducks, the suitable polymer is SLea-PAA (i.e., a 1-3 linkage between galactose and glucosamine is optimal). This finding is in accord with the data that H13 viruses isolated from the gulls differ based on their ability to interact with polymer sialylglycoconjugates. The affinity to all three polymers is uniform, and the presence of GlcNAc-linked fucose does not prevent the binding. A comparative analysis of six sequenced HA H13 viruses and other subtype viruses showed presence of substantial differences in the composition of amino acids of this region in H13 viruses.

A comparative study of the hemagglutinin (HA) receptor binding site (RBS) of a number of H13 influenza viruses isolated from Laridae family of birds (gulls) and other influenza viruses obtained from the Anatidae family (ducks) was conducted. The affinity of all viruses to alpha N-acetylneuraminic acid (Neu5Ac alpha ), 3'sialyllactose (3'SL), and sialylglycopolymers bearing 3'-sialyl(N-acetyllactosamine) (3'SLN-PAA), [Neu5Ac alpha (2-3)Gal beta (1-4)][-Fuc alpha (1-3)]GlcNAc beta (SLe super(x)-PAA), and [Neu5Ac alpha (2-3)Gal beta (1-3)][-Fuc alpha (1-4)]GlcNAc beta (SLe super(a)-PAA), was determined. The last three polymer glycoconjugates were synthesized for determining the contribution of carbohydrate chains after the galactose link to the binding with the receptor. The difference in affinity between 3'SL and Neu5Ac alpha in all studied H13 viruses is small, which indicates a less significant role of the galactose moiety in the binding to the receptor. The results of virus binding with polymer sialylglycoconjugates indicates that the method of linking, the third monosaccharide moiety, and the presence of an extra fucose substitute in this moiety may influence the binding considerably. For viruses isolated from ducks, the suitable polymer is SLe super(a)-PAA (i.e., a 1-3 linkage between galactose and glucosamine is optimal). This finding is in accord with the data that H13 viruses isolated from the gulls differ based on their ability to interact with polymer sialylglycoconjugates. The affinity to all three polymers is uniform, and the presence of GlcNAc-linked fucose does not prevent the binding. A comparative analysis of six sequenced HA H13 viruses and other subtype viruses showed presence of substantial differences in the composition of amino acids of this region in H13 viruses.Original Abstract: Diferencias entre los sitios de interaccion de los receptores de la hemaglutinina de los virus de influenza aislados a partir de aves de las especies laridae y anatidae.Este es un estudio comparativo de los sitios de interaccion de los receptores de la hemaglutinina de varios aislados de virus de influenza del tipo H13 obtenidos a partir de aves de la familia Laridae (gaviotas) y otros virus de influenza obtenidos de aves de la familia Anatidae (patos). Se determino la afinidad de todos los virus al acido alfa N-neuraminico (Neu5Ac alpha ), a la 3' sialolactosa (3'SL) y a los sialilglicopolimeros que contienen 3'-sialil(N-acetil lactosamina) (3'SLN-PAA), [Neu5Ac alpha (2-3)Gal beta (1-4)][-Fuc alpha (1-3)]GlcNAc alpha (SLe super(x)-PAA) y [Neu5Ac alpha (2-3)Gal beta (1-3)][-Fuc alpha (1-4)]GlcNAc alpha (SLe super(a)-PAA). Los ultimos tres polimeros glucoconjugados mencionados fueron sintetizados con el fin de determinar la contribucion de las cadenas de azucares anadidas despues de la galactosa en relacion con la union al receptor. La diferencia en afinidad entre el 3' SL y el Neu5Ac alpha en todos los virus del tipo H13 estudiados fue pequena, lo que indica que la galactosa juega un papel menos significativo en la union al receptor. Los resultados de la interaccion de los virus con los polimeros sialilglucoconjugados indican que la forma quimica con un tercer residuo de monosacarido y la presencia de una sustitucion extra de fucosa en este residuo puede influenciar la union al receptor de una manera significativa. Para los virus aislados de patos el polimero mas adecuado fue el SLe super(a)-PAA, o sea una union 1-3 entre la galactosa y la glucosamina es la forma quimica optima. Este hallazgo concuerda con los datos obtenidos en estudios con virus del tipo H13 aislados a partir de gaviotas, los cuales difieren en su capacidad para interactuar con polimeros sialilglucoconjugados. La afinidad para los tres polimeros es uniforme y la presencia de un residuo de fucosa unido a GlcNac no impide la union al receptor. Un analisis comparativo de la secuencia de seis de los aislados del virus del tipo H13 y otros subtipos indico la presencia de diferencias sustanciales en la secuencia de aminoacidos en esta region en los virus del tipo H13.Abbreviations: 3'SL = Neu5Ac alpha (2-3)Gal beta (1-4)Glc beta , 3'SLN = Neu5Ac alpha (2-3)Gal beta (1-4)GlcNAc beta , HA = hemagglutinin, Neu5Ac alpha = alpha N-acetylneuraminic acid, PAA = polyacrylamide, RBS = receptor binding site, SLe super(x) = [Neu5Ac alpha (2-3)Gal beta (1-4)][-Fuc alpha (1-3)]GlcNAc beta , SLe super(a) = [Neu5Ac alpha (2-3)Gal beta (1-3)][-Fuc alpha (1-4)]GlcNAc beta

Changes in metabolic pathways are often associated with the development of various pathologies including cancer, inflammatory diseases, obesity and metabolic syndrome. Identification of the particular metabolic events that are dysregulated may yield strategies for pharmacologic intervention. However, such studies are hampered by the use of classic cell media that do not reflect the metabolite composition that exists in blood plasma and which cause non-physiological adaptations in cultured cells. In recent years two groups presented media that aim to reflect the composition of human plasma, namely human plasma-like medium (HPLM) and Plasmax. Here we describe that, in four different mammalian cell lines, Plasmax enhances mitochondrial respiration. This is associated with the formation of vast mitochondrial networks and enhanced production of reactive oxygen species (ROS). Interestingly, cells cultivated in Plasmax displayed significantly less lysosomes than when any standard media were used. Finally, cells cultivated in Plasmax support replication of various RNA viruses, such as hepatitis C virus (HCV) influenza A virus (IAV), severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) and several others, albeit at lower levels and with delayed kinetics. In conclusion, studies of metabolism in the context of viral infections, especially those concerning mitochondria, lysosomes, or redox systems, should be performed in Plasmax medium.

Three types of coatings (contact-based, release-based, and combined coatings with both contact-based and release-based actions) were prepared and tested for the ability to inactivate SARS-CoV-2. In these coatings, quaternary ammonium surfactants were used as active agents since quaternary ammonium compounds are some of the most commonly used disinfectants. To provide contact-based action, the glass and silicon surfaces with covalently attached quaternary ammonium cationic surfactant were prepared using a dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride modifier. Surface modification was confirmed by attenuated total reflection infrared spectroscopy, X-ray photoelectron spectroscopy (XPS), scanning electron microscopy, and contact angle measurements. The grafting density of the modifier was estimated by XPS and elemental analysis. To provide release-based action, the widely used quaternary ammonium cationic disinfectant, benzalkonium chloride (BAC), and a newly synthesized cationic gemini surfactant, C18-4-C18, were bound non-covalently to the surface either through hydrophobic or electrostatic interactions. Virus titration revealed that the surfaces with combined contact-based and release-based action and the surfaces with only release-based action completely inactivate SARS-CoV-2. Coatings containing only covalently bound disinfectant are much less effective; they only provide up to 1.25 log10 reduction in the virus titer, probably because of the low disinfectant content in the surface monolayer. No pronounced differences in the activity between the flat and structured surfaces were observed for any of the coatings under study. Comparative studies of free and electrostatically bound disinfectants show that binding to the surface of nanoparticles diminishes the activity. These data indicate that SARS-CoV-2 is more sensitive to the free disinfectants.

The virucidal activity of a series of cationic surfactants differing in the length and number of hydrophobic tails (at the same hydrophilic head) and the structure of the hydrophilic head (at the same length of the hydrophobic n-alkyl tail) was compared. It was shown that an increase in the length and number of hydrophobic tails, as well as the presence of a benzene ring in the surfactant molecule, enhance the virucidal activity of the surfactant against SARS-CoV-2. This may be due to the more pronounced ability of such surfactants to penetrate and destroy the phospholipid membrane of the virus. Among the cationic surfactants studied, didodecyldimethylammonium bromide was shown to be the most efficient as a disinfectant, its 50% effective concentration (EC50) being equal to 0.016 mM. Two surfactants (didodecyldimethylammonium bromide and benzalkonium chloride) can deactivate SARS-CoV-2 in as little as 5 s.

Papain-like protease PLpro, a domain within a large polyfunctional protein, nsp3, plays key roles in the life cycle of SARS-CoV-2, being responsible for the first events of cleavage of a polyprotein into individual proteins (nsp1–4) as well as for the suppression of cellular immunity. Here, we developed a new genetically encoded fluorescent sensor, named PLpro-ERNuc, for detection of PLpro activity in living cells using a translocation-based readout. The sensor was designed as follows. A fragment of nsp3 protein was used to direct the sensor on the cytoplasmic surface of the endoplasmic reticulum (ER) membrane, thus closely mimicking the natural target of PLpro. The fluorescent part included two bright fluorescent proteins—red mScarlet I and green mNeonGreen—separated by a linker with the PLpro cleavage site. A nuclear localization signal (NLS) was attached to ensure accumulation of mNeonGreen into the nucleus upon cleavage. We tested PLpro-ERNuc in a model of recombinant PLpro expressed in HeLa cells. The sensor demonstrated the expected cytoplasmic reticular network in the red and green channels in the absence of protease, and efficient translocation of the green signal into nuclei in the PLpro-expressing cells (14-fold increase in the nucleus/cytoplasm ratio). Then, we used PLpro-ERNuc in a model of Huh7.5 cells infected with the SARS-CoV-2 virus, where it showed robust ER-to-nucleus translocation of the green signal in the infected cells 24 h post infection. We believe that PLpro-ERNuc represents a useful tool for screening PLpro inhibitors as well as for monitoring virus spread in a culture.

Advances in medicinal chemistry have led to the development of anticancer and anti-infectious drugs. However, many types of cancer and viral infections such as hepatitis B virus or SARS-CoV-2 are still treated ineffectively. Therefore, further development of effective and selective lead compounds as potential drugs is still highly demanded. In this study, we synthesized a novel series of piperazine-substituted pyranopyridines and evaluated their anticancer and antiviral properties. Antiproliferative activity was determined in a panel of various tumor cell lines as well as non-tumor hepatic HepaRG cells. Mechanisms of cytotoxicity were assessed by fluorescent microscopy techniques. Antiviral activity was analyzed towards DNA and RNA viruses in infectious cell culture systems. Several compounds showed antiproliferative activity towards various cancer cell lines at micromolar and submicromolar concentrations. Mechanisms of cytotoxicity involve the induction of apoptosis and are not mediated via ERK1/2 pathway or oxidative stress. Several compounds exhibit selective activity against hepatitis B virus by preventing the formation of virion particles. This study led to the identification of a novel class of piperazine-substituted pyranopyridines with antiproliferative activity towards a wide range of tumor cell lines as well as the non-toxic inhibitor of HBV virion production.