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41.
42.
Alexander N. Prutkov Andrey V. Matveev Lyubov E. Grebenkina Mikhail G. Akimov Yulia V. Berezovskaya 《Nucleosides, nucleotides & nucleic acids》2020,39(7):943-963
AbstractSome 5-substituted ribavirin analogues have a high antiviral and anticancer activity, but their mechanisms of action are obviously not the same as their parent compound. The SAR studies performed on 3 (5)-substituted 1,2,4-triazole nucleosides have shown a high dependency between the structure of the 3 (5)-substituent and the level of antiviral/anticancer activity. The most active substances of the row contain coplanar with the 1,2,4-triazole ring aromatic substituent which is connected by a rigid ethynyl bond. However, the compounds with the trans-vinyl linker also had antiviral activity. We decided to study the antitumor activity of ribavirin analogues with alkyl/aryl vinyl substituents in the 5th position of the 1,2,4-triazole ring. Protected nucleoside analogues with various 5-alkylvinyl substituents were obtained by Horner-Wadsworth-Emmons reaction from the common precursor and converted to the nucleosides. Arylvinyl nucleosides were synthesised according the reported procedures. All compounds did not show significant antiproliferative activity on several tumour cell lines. Coplanar aromatic motif in the 5-substituent for the anticancer activity manifestation was confirmed. 相似文献
43.
Andrei A. Gakh Natalia Yu Anisimova Mikhail V. Kiselevsky Sergey V. Sadovnikov Ivan N. Stankov Mikhail V. Yudin Konstantin A. Rufanov Mikhail Yu Krasavin Andrey V. Sosnov 《Bioorganic & medicinal chemistry letters》2010,20(20):6149-6151
Dihydro-resveratrol (dihydro-R), a prominent polyphenol component of red wine, has a profound proliferative effect on hormone-sensitive tumor cell lines such as breast cancer cell line MCF7. We found a significant increase in MCF7 tumor cells growth rates in the presence of picomolar concentrations of this compound. The proliferative effect of dihydro-R was not observed in cell lines that do not express hormone receptors (MDA-MB-231, BT-474, and К-562). 相似文献
44.
H3N2 human influenza viruses that are resistant to horse, pig, or rabbit serum possess unique amino acid mutations in their hemagglutinin (HA) protein. To determine the molecular mechanisms of this resistance, we characterized the receptor-binding properties of these mutants by measuring their affinity for total serum protein inhibitors and for soluble receptor analogs. Pig serum-resistant variants displayed a markedly decreased affinity for total pig serum sialylglycoproteins (which contain predominantly 2-6 linkage between sialic acid and galactose residues) and for the sialyloligosaccharide 6′-sialyl(N-acetyllactosamine). These properties correlated with the substitution 186S→I in HA1. The major inhibitory activity in rabbit serum was found to be a β inhibitor with characteristics of mannose-binding lectins. Rabbit serum-resistant variants exhibited decreased sensitivity to this inhibitor due to the loss of a glycosylation sequon at positions 246 to 248 of the HA. In addition to a somewhat reduced affinity for 6′-sialyl(N-acetyllactosamine)-containing receptors, horse serum-resistant variants lost the ability to bind the viral neuraminidase-resistant 4-O-acetylated sialic acid moieties of equine α2-macroglobulin because of the mutation 145N→K/D in their HA1. These results indicate that influenza viruses become resistant to serum inhibitors because their affinity for these inhibitors is reduced. To determine whether natural inhibitors play a role in viral evolution during interspecies transmission, we compared the receptor-binding properties of H3N8 avian and equine viruses, including two strains isolated during the 1989 to 1990 equine influenza outbreak, which was caused by an avian virus in China. Avian strains bound 4-O-acetylated sialic acid residues of equine α2-macroglobulin, whereas equine strains did not. The earliest avian-like isolate from a horse influenza outbreak bound to this sialic acid with an affinity similar to that of avian viruses; a later isolate, however, displayed binding properties more similar to those of classical equine strains. These data suggest that the neuraminidase-resistant sialylglycoconjugates present in horses exert selective pressure on the receptor-binding properties of avian virus HA after its introduction into this host.Influenza A viruses possess two envelope glycoproteins:hemagglutinin (HA) and neuraminidase (NA). HA binds to cell surface sialylglycoconjugates and mediates virus attachment to target cells (19, 30). NA cleaves the α-glycosidic linkage between sialic acid and an adjacent sugar residue, facilitating elution of virus progeny from infected cells and preventing self-aggregation of the virus (1, 13). Natural sialylglycoconjugates are structurally diverse (37, 40), and the preferential recognition of distinct sialyloligosaccharides by HA and NA correlates with the host species from which the viruses are isolated (reviewed in references 19, 30, and 38; see also references 4, 6, 7, 11, and 28).The receptor-binding activity of influenza viruses can be inhibited by certain molecules present in the sera and fluid secretions of animals (see references 14 and 21 for reviews). These inhibitors are classified as α, β, and γ types based on their thermal stability, virus-neutralizing activity, and sensitivity to inactivation by NA and periodate treatments. The β inhibitors are thermolabile mannose-binding lectins that interact with the oligosaccharide moieties on viral glycoproteins. They neutralize virus by steric hindrance of HA and by activation of the complement-dependent pathway (2, 3). By contrast, the α and γ inhibitors are heat-stable sialylated glycoproteins that mimic the structure of the cellular receptors of influenza viruses and competitively block the receptor-binding sites of HA. Influenza viruses are neutralized by γ inhibitors but not by α inhibitors, which are considered to be sensitive to viral NA. However, the distinction between α and γ inhibitors is strain dependent and rather arbitrary, as described by Gottschalk et al. (14). Although inhibitors in serum or other body fluids are believed to influence the selection of influenza virus receptor variants in natural hosts, no direct experimental support for this hypothesis has been presented.A potent γ inhibitor of H2 and H3 human influenza viruses, equine α2-macroglobulin (EM), contains a Neu4,5Ac22-6Gal moiety that is insensitive to viral NA and thus resists inactivation by this enzyme (16, 24, 31). Cultivation of human H3 influenza viruses in the presence of horse serum results in the selection of variants that have a decreased affinity for the Neu5Ac2-6Gal-specific receptors due to a single amino acid substitution (226L→Q) in their HA (32, 33). One of these mutants (X31/HS strain) does not bind the Neu4,5Ac2 (4-O-acetylated sialic acid) species (25). Therefore, there are at least two mechanisms by which a virus can become resistant to the horse serum inhibitor: a change in the recognition of the type of Sia-Gal linkage, and a change in the recognition of the 4-O-acetylated sialic acid. The relative contributions of these mechanisms to the resistant phenotype are yet to be defined.We have previously shown that horse, pig, and rabbit sera all contain distinct heat-resistant inhibitors of the H3N2 human influenza virus A/Los Angeles/2/87 (LA/87), because variants resistant to these sera possess unique mutations in their HA receptor-binding regions (34). The major inhibitor in pig serum was later identified as α2-macroglobulin that contains predominantly 2-6 linkage between sialic acid and galactose (35). Gimsa et al. (12) recently showed that pig serum-resistant human and swine strains exhibit decreased affinity for human erythrocytes that had been modified to contain terminal Neu5Ac2-6Gal residues. However, the nature of the rabbit serum inhibitor and the mechanisms of influenza virus resistance to each serum inhibitor remain unknown.To understand the molecular mechanisms by which influenza viruses become resistant to horse, pig, and rabbit serum inhibitors, we compared the receptor-binding characteristics of LA/87 and its serum-resistant variants and analyzed these data in relation to the known amino acid substitutions in the HA of the mutants. We then analyzed the receptor-binding properties of viruses isolated during an equine influenza outbreak that was caused by an avian virus, in order to evaluate the influence of natural inhibitors on the evolution of virus in a new host. 相似文献
45.
Mikhail Krasavin Raivis Žalubovskis Aiga Grandāne Ilona Domračeva Petr Zhmurov 《Journal of enzyme inhibition and medicinal chemistry》2013,28(1):506-510
Abstract The hypothesis that sulfocoumarin acting as inhibitors of human carbonic anhydrase (CA, EC 4.2.1.1) cancer-associated isoforms hCA IX and – hCA XII is being able to also inhibit thioredoxin reductase was verified and confirmed. The dual targeting of two cancer cell defence mechanisms, i.e. hypoxia and oxidative stress, may both contribute to the observed antiproliferative profile of these compounds against many cancer cell lines. This unprecedented dual anticancer mechanism may lead to a new approach for designing innovative therapeutic agents. 相似文献
46.
Eugenia Voziyanova Natalia Malchin Rachelle P. Anderson Ezra Yagil Mikhail Kolot Yuri Voziyanov 《Nucleic acids research》2013,41(12):e125
Recombinase-mediated cassette exchange, or RMCE, is a clean approach of gene delivery into a desired chromosomal location, as it is able to insert only the required sequences, leaving behind the unwanted ones. RMCE can be mediated by a single site-specific DNA recombinase or by two recombinases with different target specificities (dual RMCE). Recently, using the Flp–Cre recombinase pair, dual RMCE proved to be efficient, provided the relative ratio of the enzymes during the reaction is optimal. In the present report, we analyzed how the efficiency of dual RMCE mediated by the Flp–Int (HK022) pair depends on the variable input of the recombinases—the amount of the recombinase expression vectors added at transfection—and on the order of the addition of these vectors: sequential or simultaneous. We found that both in the sequential and the simultaneous modes, the efficiency of dual RMCE was critically dependent on the absolute and the relative concentrations of the Flp and Int expression vectors. Under optimal conditions, the efficiency of ‘simultaneous’ dual RMCE reached ∼12% of the transfected cells. Our results underline the importance of fine-tuning the reaction conditions for achieving the highest levels of dual RMCE. 相似文献
47.
48.
Fang Zhao Robert Edwards Diana Dizon Kambiz Afrasiabi Jennifer R. Mastroianni Mikhail Geyfman André J. Ouellette Bogi Andersen Steven M Lipkin 《Developmental biology》2010,338(2):270-44868
Anterior Gradient 2 (AGR2) is a protein disulfide isomerase that plays important roles in diverse processes in multiple cell lineages as a developmental regulator, survival factor and susceptibility gene for inflammatory bowel disease. Here, we show using germline and inducible Agr2−/− mice that Agr2 plays important roles in intestinal homeostasis. Agr2−/− intestine has decreased goblet cell Mucin 2, dramatic expansion of the Paneth cell compartment, abnormal Paneth cell localization, elevated endoplasmic reticulum (ER) stress, severe terminal ileitis and colitis. Cell culture experiments show that Agr2 expression is induced by ER stress, and that siRNA knockdown of Agr2 increases ER stress response. These studies implicate Agr2 in intestinal homeostasis and ER stress and suggest a role in the etiology of inflammatory bowel disease. 相似文献
49.
Vadim I. Nazarov Mikhail V. Pogorelyy Ekaterina A. Komech Ivan V. Zvyagin Dmitry A. Bolotin Mikhail Shugay Dmitry M. Chudakov Yury B. Lebedev Ilgar Z. Mamedov 《BMC bioinformatics》2015,16(1)
Background
The Immunoglobulins (IG) and the T cell receptors (TR) play the key role in antigen recognition during the adaptive immune response. Recent progress in next-generation sequencing technologies has provided an opportunity for the deep T cell receptor repertoire profiling. However, a specialised software is required for the rational analysis of massive data generated by next-generation sequencing.Results
Here we introduce tcR, a new R package, representing a platform for the advanced analysis of T cell receptor repertoires, which includes diversity measures, shared T cell receptor sequences identification, gene usage statistics computation and other widely used methods. The tool has proven its utility in recent research studies.Conclusions
tcR is an R package for the advanced analysis of T cell receptor repertoires after primary TR sequences extraction from raw sequencing reads. The stable version can be directly installed from The Comprehensive R Archive Network (http://cran.r-project.org/mirrors.html). The source code and development version are available at tcR GitHub (http://imminfo.github.io/tcr/) along with the full documentation and typical usage examples. 相似文献50.
Nikolay I. Zhurilo Mikhail V. Chudinov Andrey V. Matveev Olga S. Smirnova Irina D. Konstantinova Anatoly I. Miroshnikov Alexander N. Prutkov Lyubov E. Grebenkina Natalya V. Pulkova Vitaly I. Shvets 《Bioorganic & medicinal chemistry letters》2018,28(1):11-14
The novel isosteric ribavirin analogues were synthesized by two different ways. Some of them showed significant antiviral action against hepatitis C virus (HCV), herpes simplex (HCV-1) and influenza A virus comparable to that of ribavirin itself. The data obtained confirm the proposed theory of the ribavirin possible antiviral activity mechanism related with bioisosterism. 相似文献