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Добірка наукової літератури з теми "Antiviral inhibitors"

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Опубліковано: 11 вересня 2023

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Статті в журналах з теми "Antiviral inhibitors"

1

Frederickson, Robert. "Antiviral protease inhibitors." Nature Biotechnology 17, no. 12 (December 1999): 1150. http://dx.doi.org/10.1038/70677.

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2

Wang, Q. May, Robert B. Johnson, Louis N. Jungheim, Jeffrey D. Cohen, and Elcira C. Villarreal. "Dual Inhibition of Human Rhinovirus 2A and 3C Proteases by Homophthalimides." Antimicrobial Agents and Chemotherapy 42, no. 4 (April 1, 1998): 916–20. http://dx.doi.org/10.1128/aac.42.4.916.

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ABSTRACT The 2A and 3C proteases encoded by human rhinoviruses (HRVs) are attractive targets for antiviral drug development due to their important roles in viral replication. Homophthalimides were originally identified as inhibitors of rhinovirus 3C protease through our screening effort. Previous studies have indicated that the antiviral activity of certain homophthalimides exceeded their in vitro inhibitory activity against the viral 3C protease, suggesting that an additional mechanism might be involved. Reported here is the identification of homophthalimides as potent inhibitors for another rhinovirus protease, designated 2A. Several homophthalimides exhibit time-dependent inhibition of the 2A protease in the low-micromolar range, and enzyme-inhibitor complexes were identified by mass spectrometry. Compound LY343814, one of the most potent inhibitors against HRV14 2A protease, had an antiviral 50% inhibitory concentration of 4.2 μM in the cell-based assay. Our data reveal that homophthalimides are not only 3C but also 2A protease inhibitors in vitro, implying that the antiviral activity associated with these compounds might result from inactivation of both 2A and 3C proteases in vivo. Since the processing of the viral polyprotein is hierarchical, dual inhibition of the two enzymes may result in cooperative inhibition of viral replication. On the basis of the current understanding of their enzyme inhibitory mechanism, homophthalimides, as a group of novel nonpeptidic antirhinovirus agents, merit further structure-action relationship studies.
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3

Mello, Chris, Esmeralda Aguayo, Madeleine Rodriguez, Gary Lee, Robert Jordan, Tomas Cihlar, and Gabriel Birkus. "Multiple Classes of Antiviral Agents ExhibitIn VitroActivity against Human Rhinovirus Type C." Antimicrobial Agents and Chemotherapy 58, no. 3 (December 23, 2013): 1546–55. http://dx.doi.org/10.1128/aac.01746-13.

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ABSTRACTHuman rhinovirus type C (HRV-C) is a newly discovered enterovirus species frequently associated with exacerbation of asthma and other acute respiratory conditions. Until recently, HRV-C could not be propagatedin vitro, hampering in-depth characterization of the virus replication cycle and preventing efficient testing of antiviral agents. Herein we describe several subgenomic RNA replicon systems and a cell culture infectious model for HRV-C that can be used for antiviral screening. The replicon constructs consist of genome sequences from HRVc15, HRVc11, HRVc24, and HRVc25 strains, with the P1 capsid region replaced by aRenillaluciferase coding sequence. Following transfection of the replicon RNA into HeLa cells, the constructs produced time-dependent increases in luciferase signal that can be inhibited in a dose-dependent manner by known inhibitors of HRV replication, including the 3C protease inhibitor rupintrivir, the nucleoside analog inhibitor MK-0608, and the phosphatidylinositol 4-kinase IIIβ (PI4K-IIIβ) kinase inhibitor PIK93. Furthermore, with the exception of pleconaril and pirodavir, the other tested classes of HRV inhibitors blocked the replication of full-length HRVc15 and HRVc11 in human airway epithelial cells (HAEs) that were differentiated in the air-liquid interface, exhibiting antiviral activities similar to those observed with HRV-16. In summary, this study is the first comprehensive profiling of multiple classes of antivirals against HRV-C, and the set of newly developed quantitative HRV-C antiviral assays represent indispensable tools for the identification and evaluation of novel panserotype HRV inhibitors.
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4

Vinson, Valda. "Promising antiviral protease inhibitors." Science 368, no. 6497 (June 18, 2020): 1324.2–1324. http://dx.doi.org/10.1126/science.368.6497.1324-b.

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5

Morales Vasquez, Desarey, Jun-Gyu Park, Ginés Ávila-Pérez, Aitor Nogales, Juan Carlos de la Torre, Fernando Almazan, and Luis Martinez-Sobrido. "Identification of Inhibitors of ZIKV Replication." Viruses 12, no. 9 (September 18, 2020): 1041. http://dx.doi.org/10.3390/v12091041.

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Zika virus (ZIKV) was identified in 1947 in the Zika forest of Uganda and it has emerged recently as a global health threat, with recurring outbreaks and its associations with congenital microcephaly through maternal fetal transmission and Guillain-Barré syndrome. Currently, there are no United States (US) Food and Drug Administration (FDA)-approved vaccines or antivirals to treat ZIKV infections, which underscores an urgent medical need for the development of disease intervention strategies to treat ZIKV infection and associated disease. Drug repurposing offers various advantages over developing an entirely new drug by significantly reducing the timeline and resources required to advance a candidate antiviral into the clinic. Screening the ReFRAME library, we identified ten compounds with antiviral activity against the prototypic mammarenavirus lymphocytic choriomeningitis virus (LCMV). Moreover, we showed the ability of these ten compounds to inhibit influenza A and B virus infections, supporting their broad-spectrum antiviral activity. In this study, we further evaluated the broad-spectrum antiviral activity of the ten identified compounds by testing their activity against ZIKV. Among the ten compounds, Azaribine (SI-MTT = 146.29), AVN-944 (SI-MTT = 278.16), and Brequinar (SI-MTT = 157.42) showed potent anti-ZIKV activity in post-treatment therapeutic conditions. We also observed potent anti-ZIKV activity for Mycophenolate mofetil (SI-MTT = 20.51), Mycophenolic acid (SI-MTT = 36.33), and AVN-944 (SI-MTT = 24.51) in pre-treatment prophylactic conditions and potent co-treatment inhibitory activity for Obatoclax (SI-MTT = 60.58), Azaribine (SI-MTT = 91.51), and Mycophenolate mofetil (SI-MTT = 73.26) in co-treatment conditions. Importantly, the inhibitory effect of these compounds was strain independent, as they similarly inhibited ZIKV strains from both African and Asian/American lineages. Our results support the broad-spectrum antiviral activity of these ten compounds and suggest their use for the development of antiviral treatment options of ZIKV infection.
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6

Sepúlveda, Claudia Soledad, Cybele Carina García, and Elsa Beatriz Damonte. "Inhibitors of Nucleotide Biosynthesis as Candidates for a Wide Spectrum of Antiviral Chemotherapy." Microorganisms 10, no. 8 (August 12, 2022): 1631. http://dx.doi.org/10.3390/microorganisms10081631.

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Emerging and re-emerging viruses have been a challenge in public health in recent decades. Host-targeted antivirals (HTA) directed at cellular molecules or pathways involved in virus multiplication represent an interesting strategy to combat viruses presently lacking effective chemotherapy. HTA could provide a wide range of agents with inhibitory activity against current and future viruses that share similar host requirements and reduce the possible selection of antiviral-resistant variants. Nucleotide metabolism is one of the more exploited host metabolic pathways as a potential antiviral target for several human viruses. This review focuses on the antiviral properties of the inhibitors of pyrimidine and purine nucleotide biosynthesis, with an emphasis on the rate-limiting enzymes dihydroorotate dehydrogenase (DHODH) and inosine monophosphate dehydrogenase (IMPDH) for which there are old and new drugs active against a broad spectrum of pathogenic viruses.
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7

De Nicolò, Amedeo, Marco Simiele, Andrea Calcagno, Adnan Mohamed Abdi, Stefano Bonora, Giovanni Di Perri, and Antonio D'Avolio. "Intracellular Antiviral Activity of Low-Dose Ritonavir in Boosted Protease Inhibitor Regimens." Antimicrobial Agents and Chemotherapy 58, no. 7 (May 5, 2014): 4042–47. http://dx.doi.org/10.1128/aac.00104-14.

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ABSTRACTProtease inhibitors are largely used for the treatment of HIV infection in combination with other antiretroviral drugs. Their improved pharmacokinetic profiles can be achieved through the concomitant administration of low doses of ritonavir (RTV), a protease inhibitor currently used as a booster, increasing the exposure of companion drugs. Since ritonavir-boosted regimens are associated with long-term adverse events, cobicistat, a CYP3A4 inhibitor without antiviral activity, has been developed. Recently, high intracellular concentrations of ritonavir in lymphocytes and monocytes were reported even when ritonavir was administered at low doses, so we aimed to compare its theoretical antiviral activity with those of the associated protease inhibitors. Intracellular concentrations of ritonavir and different protease inhibitors were determined through the same method. Inhibitory constants were obtained from the literature. The study enrolled 103 patients receiving different boosted protease inhibitors, darunavir-ritonavir 600 and 100 mg twice daily and 800 and 100 mg once daily (n= 22 and 4, respectively), atazanavir-ritonavir 300 and 100 mg once daily (n= 40), lopinavir-ritonavir 400 and 100 mg twice daily (n= 21), or tipranavir-ritonavir 500 and 200 mg twice daily (n= 16). According to the observed concentrations, we calculated the ratios between the intracellular concentrations of ritonavir and those of the companion protease inhibitor and between the theoretical viral protease reaction speeds with each drug, with and without ritonavir. The median ratios were 4.04 and 0.63 for darunavir-ritonavir twice daily, 2.49 and 0.74 for darunavir-ritonavir once daily, 0.42 and 0.74 for atazanavir-ritonavir, 0.57 and 0.95 for lopinavir-ritonavir, and 0.19 and 0.84 for tipranavir-ritonavir, respectively. Therefore, the antiviral effect of ritonavir was less than that of the concomitant protease inhibitors but, importantly, mostly with darunavir. Thus, furtherin vitroandin vivostudies of the RTV antiviral effect are warranted.
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8

Holý, Antonín, Ivan Votruba, and Erik De Clercq. "Structure-activity studies on open-chain analogues of nucleosides: Inhibition of S-adenosyl-L-homocysteine hydrolase and antiviral activity 1. Neutral open-chain analogues." Collection of Czechoslovak Chemical Communications 50, no. 1 (1985): 245–61. http://dx.doi.org/10.1135/cccc19850245.

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Over 70 alkyl derivatives of purine bases were examined for their inhibitory effects toward rat liver S-adenosyl-L-homocysteine hydrolase and their antiviral activity. The following structural features must be fulfilled by an inhibitor of SAH-hydrolase: an intact adenine moiety, an alkyl chain bound at the 9-position and bearing a vicinal diol at the 2',3'-position, with 2S configuration. An additional substitution at the 3-position lowers or annihilates the inhibitory activity. The enzyme inhibition is reversible. Some of the compounds are substrates of adenosine aminohydrolase. All inhibitors of SAH-hydrolase exhibit antiviral activity, e.g. against vesicular stomatitis virus and vaccinia virus in cell culture, and this antiviral correlates with the inhibition of SAH-hydrolase.
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9

Hewajuli, Dyah Ayu, and NLPI Dharmayanti. "Efficacy, Mechanism and Antiviral Resistance of Neuraminidase Inhibitors and Adamantane against Avian Influenza." Indonesian Bulletin of Animal and Veterinary Sciences 29, no. 2 (December 4, 2019): 61. http://dx.doi.org/10.14334/wartazoa.v29i2.1951.

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Vaccination and antiviral drug are often used to control influenza. However, the effectiveness of vaccine was impaired due to the emergence of new variant of virus strain. Antiviral drug consists of prophylactic and curative substances, namely M2 ion channel inhibitors (adamantane; amantadine and rimantadine) and neuraminidase (NA) inhibitors (NAIs; oseltamivir, zanamivir, peramivir, laninamivir). The synthesis and modification of antiviral neuraminidase (NA) inhibitors (NAIs) and adamantanes increased the antiviral effectiveness. The mechanism of the neuraminidase inhibitor is to prevent influenza infection by inhibiting the release of the virus from internal cells. Adamantane is antiviral drug that selectively inhibits the flow of H+ ions through M2 protein to prevent the uncoating virus particles getting into the endosome. The substitution of (H275Y, S247N, I223L, K150N, R292K, I222T, R152K, R118K, E119V) on NA protein caused resistance of avian influenza virus against the neuraminidase inhibitor. The combination of mutations (S247N, I223L, K150N) increased the resistance of influenza A (H5N1) virus. The diffusion of adamantane resistance varies among HA subtypes, the species of host, the period of isolation, and region. Mutations at residues of 26, 27, 30, 31 or 34 transmembrane M2 protein caused adamantane resistance. The unique substitution (V27I) of M2 protein of clade 2.3.2 H5N1 subtype isolated in Indonesia in 2016 has been contributed to the amantadine resistance. Antiviral combination of M2 ion channel inhibitors and neuraminidase (NA) inhibitors is effective treatments for the resistance.
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10

Hayden, Frederick G. "Perspectives on antiviral use during pandemic influenza." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 356, no. 1416 (December 29, 2001): 1877–84. http://dx.doi.org/10.1098/rstb.2001.1007.

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Antiviral agents could potentially play a major role in the initial response to pandemic influenza, particularly with the likelihood that an effective vaccine is unavailable, by reducing morbidity and mortality. The M2 inhibitors are partially effective for chemoprophylaxis of pandemic influenza and evidence from studies of interpandemic influenza indicate that the neuraminidase inhibitors would be effective in prevention. In addition to the symptom benefit observed with M2 inhibitor treatment, early therapeutic use of neuraminidase inhibitors has been shown to reduce the risk of lower respiratory complications. Clinical pharmacology and adverse drug effect profiles indicate that the neuraminidase inhibitors and rimantadine are preferable to amantadine with regard to the need for individual prescribing and tolerance monitoring. Transmission of drug-resistant virus could substantially limit the effectiveness of M2 inhibitors and the possibility exists for primary M2 inhibitor resistance in a pandemic strain. The frequency of resistance emergence is lower with neuraminidase inhibitors and mathematical modelling studies indicate that the reduced transmissibility of drug-resistant virus observed with neuraminidase inhibitor-resistant variants would lead to negligible community spread of such variants. Thus, there are antiviral drugs currently available that hold considerable promise for response to pandemic influenza before a vaccine is available, although considerable work remains in realizing this potential. Markedly increasing the quantity of available antiviral agents through mechanisms such as stockpiling, educating health care providers and the public and developing effective means of rapid distribution to those in need are essential in developing an effective response, but remain currently unresolved problems.
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Більше джерел

Дисертації з теми "Antiviral inhibitors"

1

Li, Weikuan Schneller Stewart W. "Seeking mRNA methylation inhibitors as antiviral agents." Auburn, Ala, 2008. http://hdl.handle.net/10415/1540.

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2

ourahmane, amine. "Discovery and Characterization of Cytomegalovirus Inhibitors using Reporter-based Antiviral Assays." VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/5013.

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ABSTRACT DISCOVERY AND CHARACTERIZATION OF CYTOMEGALOVIRUS INHIBITORS USING REPORTER-BASED ANTIVIRAL ASSAYS By Amine Ourahmane, MS A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University. Virginia Commonwealth University, August 2017 Major Director: Michael McVoy, Ph.D. Professor, Department of Pediatrics and Microbiology and Immunology Human cytomegalovirus (HCMV), a member of the herpesvirus family, causes significant disease in immunocompromised patients and is the major infectious cause of birth defects when acquired congenitally. Current HCMV antivirals are suboptimal due to modest potency, significant toxicities, and emergence of resistance. Because HCMV does not infect non-human species, related animal cytomegaloviruses are used as animal models. Of the small animal cytomegaloviruses only guinea pig cytomegalovirus (GPCMV) has been found to cross the placenta to cause fetal infection and disease. Thus, the GPCMV/guinea pig model of congenital infection can be used to study the effectiveness of vaccines or small molecule inhibitors in preventing or treating congenital infections. However, not all antivirals that inhibit HCMV are active against GPCMV. In Aim 1 of the current studies a luciferase-based assay was developed and used to determine the sensitivity of GPCMV to three novel inhibitory compounds, BDCRB, BAY 38-4766, and letermovir, which block DNA maturation of HCMV by targeting the viral terminase complex. BDCRB and BAY 38-4766 were active against GPCMV.Unfortunately, letermovir, which recently completed phase 3 clinical testing, was not active against GPCMV at concentrations up to 100 mM. In Aim 2 the mechanism of action of BDCRB against GPCMV was explored by characterizing an L406P mutation in the GP89 terminase subunit that had been previously identified in a BDCRB-resistant GPCMV. In silico homology modeling was used to identify the location of the L406P mutation in a predicted 3-D structure of GP89. That it was not located near a putative BDCRB-binding pocket (which was predicted based on confirmed resistance mutations in the homologous HCMV UL89 subunit) suggested that L406P may not confer BDCRB resistance in GPCMV. That L406P does not confer BDCRB resistance was confirmed by genetic transfer of the L406 mutation into an otherwise wild type GPCMV background and demonstration, using the luciferase-based assay, that the IC50 of BDCRB was not significantly altered (i.e., the virus containing the L406 mutation was not resistant to BDCRB). In Aim 3 a green fluorescent protein-based assay was used to evaluate four candidate compounds for antiviral activity against HCMV. These highly positively charged compounds, TriplatinNC, DiplatinNC, [Pt(dien)(Xan)]2+ and Werner’s Complex, were hypothesized to interfere with viral binding to cell surface glycosaminoglycans and thereby interfere with viral attachment and subsequent entry.
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3

Nevers, Quentin. "Développement d'une nouvelle famille d'inhibiteurs de cyclophilines à large spectre antiviral et étude de leurs mécanismes d'action dans les infections par le Virus de l'Hépatite C et les Coronavirus." Thesis, Paris Est, 2018. http://www.theses.fr/2018PESC0013/document.

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Les dernières décennies ont été marquées par l’émergence ou la réémergence d’un nombre croissant de virus pathogènes. Malheureusement, les antiviraux actuellement sur le marché ciblent un nombre restreint de virus ; il y a donc un besoin urgent de développer des antiviraux à large spectre. Les cyclophilines sont des protéines cellulaires impliquées dans un grand nombre de processus biologiques, qui possèdent une activité enzymatique peptidyl-prolyl cis-trans isomérase (PPIase). Elles sont également impliquées dans la réplication de virus appartenant à des familles éloignées et constituent donc une cible de choix pour le développement d'antiviraux à large spectre. Toutefois, les inhibiteurs de cyclophilines disponibles possèdent de nombreux inconvénients qui rendent leur utilisation clinique difficile.Par une stratégie de "fragment-based drug design", nous avons généré une nouvelle famille d'inhibiteurs de cyclophilines, les SMCypI ("Small-Molecule Cyclophilin Inhibitors"), complètement différents de tous les inhibiteurs de cyclophilines existants. La cristallographie de ces composés a montré qu'ils se fixaient dans les deux poches voisines du site actif des cyclophilines et qu'ils inhibaient leur activité PPIase. Ces composés n’étaient pas immunosuppressifs et bloquaient in vitro l'infection par le VIH, le VHC et les Coronavirus.L'activité anti-VHC du C31, composé le plus actif sur l'activité PPIase des cyclophilines, a été caractérisée. Le C31 était un inhibiteur pan-génotypique du VHC, doté d’une haute barrière contre la résistance et présentant une activité additive avec les inhibiteurs du VHC approuvés. Nous avons montré que le C31 bloquait l'infection par le VHC en rompant l'interaction entre la protéine virale NS5A et la cyclophiline A de façon PPIase-dépendante. Enfin, le C31 était actif sur la réplication des virus zika, de la dengue, de la fièvre jaune et du Nil Occidental.L'activité des SMCypI a été caractérisée sur l'infection par le Coronavirus 229E. De manière intéressante, l’inhibition de l’activité PPIase était nécessaire, mais pas suffisante pour l’activité antivirale. Une étude de la relation structure-activité des composés a révélé qu'un groupement chimique situé à l'interface entre les deux poches du site actif des cyclophilines jouait un rôle clé dans l'effet anti-coronavirus. Le F836 a été identifié comme le composé le plus actif, qui bloquait l'effet cytopathique et la quantité d'ARN du HCoV-229E avec la même efficacité que l'alisporivir, sans toxicité associée. Ce composé bloquait l'entrée du HCoV-229E après l'attachement du virus à la surface cellulaire, et était également actif sur l'entrée des HCoV-OC43 et du MERS-CoV. Nous avons par la suite démontré l’association de la cyclophiline A avec les particules virales. Par l'utilisation de la technologie CRISPR-Cas9, des cellules invalidées pour la cyclophiline A ont été générées. La cyclophiline A apparaissait nécessaire pour l'infection par HCoV-229E et la cible de l'effet antiviral du F836.Les SMCypI constituent un outil pour la compréhension des mécanismes par lesquels les cyclophilines modulent les infections virales et représentent des candidats crédibles pour le développement futur d'antiviraux à large spectre
Over the past decades, an increasing number of viruses has emerged or re-emerged in humans. Unfortunately, currently approved antiviral drugs target a small set of viruses. Thus, there is an urgent need for the development of broad-spectrum antiviral drugs.Cyclophilins are cellular proteins involved in a large number of biological processes, and in different viral lifecycles from unrelated families. They appear as a potential target for the development of broad-spectrum antiviral approaches. However, currently available cyclophilin inhibitors have drawbacks which limit their clinical use.By means of "fragment-based drug design", we generated a new class of small-molecule cyclophilin inhibitors (SMCypI), unrelated with those already available. Cristallographic studies revealed that the SMCypIs bind to two close pockets of the active site and inhibit cyclophilin PPIase activity. These compounds do not bear immunosuppressive properties and inhibit the replication of HIV, HCV and coronaviruses in vitro.We characterized the anti-HCV activity of C31, the most potent inhibitor of cyclophilin PPIase activity. C31 had pan-genotypic HCV inhibitor properties, with a high barrier to resistance and additive effects with currently approved anti-HCV agents. C31 blocked HCV replication by disrupting the interaction between the nonstructural viral protein NS5A and cyclophilin A in a PPIase-dependent manner. Finally, C31 was active on zika, yellow fever, dengue and West-Nile virus infections.The antiviral activity of the SMCypIs has then been characterized on HCoV-229E infection. Interestingly, PPIase inhibition was necessary, but not sufficient for antiviral effect. A structure-activity relationship study identified a key moiety in the SMCypIs at the interface between the two cyclophilin pockets. F836 has been identified as the most potent compound which inhibited both the cytopathic effect and the intracellular RNA of HCoV-229E without associated cytotoxicity and as potently as alisporivir. This compound targeted HCoV-229E entry at a post-attachment step and was also active on HCoV-OC43 and MERS-CoV strains. We then demonstrated that cyclophilin A was associated with viral particles. By means of CRISPR-Cas9, cell lines depleted for cyclophilin A were generated. Cyclophilin A was identified as a proviral factor for HCoV-229E and was partially involved in F836 antiviral effect. Cyclophilin A expression level was drastically decreased by infection.SMCypIs represent a unique tool to decipher the cellular and molecular mechanisms by which cyclophilins interfere with viral lifecycles, as well as drugable compounds that could find an indication as broad-spectrum antiviral drugs
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4

González-Ortega, Emmanuel. "Resistance to HIV entry inhibitors: signature mutations as tool guide for the identification of new antiviral agents." Doctoral thesis, Universitat de Barcelona, 2012. http://hdl.handle.net/10803/84059.

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Анотація:
There are several reasons to celebrate the latest advances in the treatment of the infection with HIV. According to the Joint United Nations Programme on HIV/AIDS, the number of new infections dropped by 15%; there is also a decrease by 22% in the number of deaths related to HIV/AIDS. Nevertheless, there are new emerging challenges, i.e. the transmission of drug-resistant HIV-1 strains. Therefore, there is a demand for the continued research for new and more potent antiretroviral agents. The entry of HIV into the cell implies a complex and well-orchestrated series of steps in which both viral and cellular molecules are implied, ending with the production of new viral particles. The HIV gp120 glycoprotein binds to the cellular CD4 receptor and to a chemokine receptor, inducing structural rearrangements that continue with the cellular and viral membrane fusion mediated by the HIV glycoprotein gp41. Hence, the entry of HIV is an essential step of the viral replication that offers an open path for the design of new antiviral compounds that could be added to the repertory of drugs used in the treatment of HIV infection. In coincidence with the recent and highly relevant information of the fusion mechanism occurring during the viral entry, the design of new fusion inhibitors has become one of the most promising and debated areas in the study of entry inhibitors. ADS-J1 was originally selected to bind to gp41 and to inhibit the fusion of membranes. In several assays, including the generation of HIV strains resistant to ADS-J1, our laboratory has proved that ADS-J1 interact with gp120 instead of gp41. A more recent publication suggested that ADS-J1 binds to the pocket region of gp41 preventing the infection by the virus. Here, we confirmed that ADS-J1 interacts with gp120 instead of gp41. Recombination of gp120 into a wild type HIV-1 backbone restored the resistant phenotype. Moreover, time of addition assays clearly demonstrated that ADS-J1 does not interact with gp41. VIRIP was identified as a natural peptide present in human hemofiltrate that inhibits the HIV gp41-mediated membrane fusion. It was suggested that VIRIP interact with the fusion peptide in gp41, therefore blocking the fusion of membranes. With the objective to determine the precise mode of action of VIRIP, we generated a HIV-1 virus resistant to VIR-353, an analogue of VIRIP. Additionally, we determined the most relevant combination of mutations for the resistant phenotype. Recent studies have shown the effectivity of VIR-576, a peptide closely related to VIRIP and VIR-353 in a clinical trial phase I/II. The resistance to VIRIP/VIR-353 took a long time to emerge, suggesting a high genetic barrier to resistance. The mutations responsible for the resistant phenotype affected in large scale the replicative capacity of the virus, nevertheless, several compensatory mutations restored the viral fitness, while the resistance to VIR-353 was unaltered. The antiviral combination of VIR-353 and T20 showed an additive effect in inhibiting viral replication, indicating that VIR-353 appeared no to affect the binding of T20 to gp41 in its antiviral activity, the combination of the two fusion inhibitors showed an additive effect in inhibiting viral replication. In general, our results evidence the plasticity of the HIV envelope glycoproteins. This plasticity is highly remarked when the virus replicates under drug selective pressure, which imposes an additional genetic barrier for the virus to overcome.
ADS‐J1 ha estat seleccionat per unir‐se a gp41 i inhibir la fusió de les membranes. A través de diversos assajos, incloent la generació de soques resistents a ADS‐J1, el nostre laboratori va demostrar que ADS‐J1 interactua amb gp120 i no amb gp41. Una publicació posterior va suggerir que ADS‐J1 s’uneix a la ‘pocket‐region’ de gp41, prevenint l’infecció pel virus. En el present treball, nosaltres confirmem que ADSJ1 interactua amb gp120 i no amb gp41 i que la recombinació de gp120 en un VIH silvestre restitueix el fenotip resistent. Assajos de temps de addició van demostrar clarament que ADS‐J1 no interactua amb gp41. VIRIP va ser identificat com un pèptid natural present en el hemofiltrat humà capaç d’inhibir la fusió de membranes operada per gp41 del VIH. Es va suggerir que VIRIP interactua amb el pèptid de fusió de gp41, bloquejant la fusió de les membranes. Nosaltres hem generat un virus resistent a VIR‐353, un anàleg de VIRIP. Addicionalment, hem determinat la combinació de mutacions que generen el fenotip resistent. Estudis recents van mostrar l'efectivitat de VIR‐576, un pèptid amb alta similitud a VIRIP i VIR‐353 en un assaig clínic fase I/II. La resistència a VIRIP/VIR‐353 va requerir un període de temps llarg per emergir, la qual cosa suggereix una elevada barrera genètica a la resistència. Les mutacions responsables del fenotip resistent van afectar en greument la capacitat replicativa del virus, no obstant això, diverses mutacions compensatòries van restaurar‐ne la capacitat replicativa, mantenint intacta la resistència a VIR‐353. L’activitat antiviral de T20 no sembla afectada per VIR‐353, la combinació dels dos inhibidors de fusió van mostrar un efecte additiu en la inhibició de la replicació. En general, els nostres resultats evidencien la plasticitat de les glicoproteïnes de l'embolcall del VIH. Aquesta plasticitat es realça quan el virus replica sota la pressió selectiva imposada per fàrmacs que inhibeixen la replicació viral, la qual cosa afegeix una barrera genètica addicional a ser superada pel virus.
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5

Howe, Jonathon David. "Antiviral mechanisms of small molecules targeting the endoplasmic reticulum and Golgi apparatus." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:04368b4b-2fd3-4fc7-8f89-ec39cd87e37d.

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N-linked glycosylation is the most common form of post-translational modification in nature and is essential to almost all enveloped viruses, including members of the Flaviviridae family. The host cell N-linked glycoprotein processing pathway is utilised by these viruses and as such has long been identified as a potential target for the development of antiviral drugs. Here, the antiviral mechanisms of three classes of small molecules targeting the secretory pathway and altering viral envelope glycosylation are investigated, using the HCV surrogate model, BVDV. The antiviral activity of imino sugars, principally through α-glucosidase inhibition, is well-characterised and here, a group of novel adamantyl coupled imino sugars are investigated and demonstrated to inhibit ER α glucosidases, which correlates with their antiviral activity against BVDV. Additionally, BVDV is used to study the antiviral mechanism of action of nitazoxanide. Nitazoxanide, the parent compound of the thiazolide class of structures, is a broadly antimicrobial compound with antiviral activity against HBV, HCV, influenza, JEV and others. Here, nitazoxanide is shown to be antiviral against BVDV by inducing Ca2+ release from ATP-sensitive intracellular calcium stores, disrupting ER-Golgi trafficking and inhibiting complex glycan formation. Finally, the potential of Golgi endo-α-mannosidase as an antiviral target is explored, using the endomannosidase inhibitor glucose-isofagomine in conjunction with the imino sugar α-glucosidase inhibitor NAP-DNJ. Endomannosidase is shown to be a valid antiviral target for BVDV, both alone and in combination with α-glucosidase inhibition, and is utilised by viral glycoproteins to acquire complex glycan structure, even in the absence of α-glucosidase inhibition. Altogether, this work furthers our understanding of the varied antiviral mechanisms of small molecules targeting the secretory pathway, enhancing the search for novel antiviral drugs directed against host cell machinery.
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6

Hoyte, Ashley Christopher. "Molecular Mechanisms for Antiviral Activities and HIV-1 Resistance to Allosteric Integrase Inhibitors." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1543436136541123.

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7

Swaminathan, Kavya. "Novel anthocyanin inhibitors to influenza neuraminidase and monitioring antiviral resistance by mass spectrometry." Thesis, The University of Sydney, 2013. http://hdl.handle.net/2123/10220.

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A novel matrix assisted laser desorption ionization (MALDI) mass spectrometry based approach to study the binding of inhibitors to the influenza virus neuraminidase is described. The approach was shown to successfully be able to localize the binding of the known inhibitors of the viral neuraminidase – zanamivir and 2-deoxy-2,3-didehydro-N-acetylneuraminic acid, confirmed from the analysis of available X-ray crystal structures. The approach was extended to study the binding of an elderberry anthocyanin – cyanidin-3-sambubiocide to the neuraminidase, in parallel with computational approaches. Results revealed for the first time the molecular basis for the anthocyanidin’s neuraminidase inhibitory and by showing its binding within the neuraminidase 430-cavity, remote from residues known to regulate neuraminidase resistance. The results obtained herein provide a framework for the development of a new class of antivirals against influenza without this susceptibility. As an integral part of the anti-influenza drug development strategy a new phylogenetic approach for the surveillance of drug resistance and newly emerging strains is presented. It utilizes mass spectral data produced from proteolytic digestion of proteins, rather than gene/translated gene sequences to chart the evolutionary history of organisms. The concept and validity of the approach is demonstrated using theoretical and experimental mass data of the influenza hemagglutinin and neuraminidase. The ability of these trees to accurately cluster viral proteins from drug resistant strains is also shown and its relevance for surveillance of novel strains and drug-resistant mutants is also established by demonstrating their ability to accurately place experimentally derived mass data on mass trees. Given that the mass data can be generated more rapidly than gene sequences, mass trees offer new opportunities and advantages for phylogenetic analysis.
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8

LUCIA, FALSITTA. "DDX3, a new frontier in broad-spectrum antiviral therapy: synthesis of potential inhibitors." Doctoral thesis, Università di Siena, 2020. http://hdl.handle.net/11365/1095615.

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Viral infections inflict many serious human diseases with very high mortality rates. New drug-resistant strains are continually emerging due to the high viral mutation rate, which makes necessary to develop novel potent antivirals. Targeting cellular cofactor essential for the replication of different viruses but not for the cells represents a new strategy to combat infectious diseases and offers a higher genetic barrier to the development of the resistance. The DEAD-box RNA helicase DDX3 is a multifunctional protein involved in many aspects of RNA metabolism, including transcription, splicing, mRNA nuclear export, translation, RNA decay and ribosome biogenesis. DDX3 is a human host factor required for the replication of several DNA and RNA such as herpes virus, human immunodeficiency virus type 1, hepatitis C virus, Dengue virus and West Nile virus. Given the multifaceted functions of DDX3, this host factor represents a promising target to develop compounds with broad spectrum antiviral activity. In the last few years Prof. Botta’s research group has been identified several inhibitors of DDX3 proteins. From a medicinal chemistry point of view, DDX3 has multiple enzymatic activities, ATPase and RNA helicase, and functional domains that may be targeted by potential inhibitors. Prof. Botta’s research group, designed and validated the first small molecule DDX3 inhibitors specifically designed to target its RNA binding site (16d with anti-helicase activity against DDX3 IC50 = 0.3 μM). Pursuing this research line, a structure-based optimization process was prosecuted, resulting in the identification of a novel compound with the 1,2,4-oxadiazole nucleus UVR40, with anti-helicase activity against DDX3 IC50 = 0.13 μM. Thus, a small library of UVR40 derivatives has been designed by our computation group and synthesized during my PhD with the purpose to enlarge SAR knowledge, enhance its ADME properties and improve its activity profile. At the same time, with the attempt to enlarge our library of DDX3 inhibitors, Prof. Botta’s group built a novel library of “hybrid” compounds starting from the structures of two hit compounds previously discovered, 16d member of the urea series, and UVR06 characterized by a sulfonamide moiety. The novel library was synthesized, validated on the target enzyme, and evaluated against the West Nile virus (WNV) infection.
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9

Gerace, Martina. "In search of new antiviral targets: Design and synthesis of new inhibitors of ZIKV Mtase and potential inhibitors of IMPDH." Doctoral thesis, Università di Siena, 2023. https://hdl.handle.net/11365/1227194.

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Viral infections are a leading cause of death worldwide. In 2016, WHO declared a public health emergency due to the spread of the Zika virus (ZIKV). In addition, the recent link between this infection and the clustered incidence of microcephaly and other neurological disorders represents a public health emergency of international significance. An effective strategy to address this emergency could be the identification and development of new antiviral agents against the NS5 protein of ZIKV that specifically target the methyltransferase (Mtase) domain. When this enzyme is blocked, the virus cannot cap the RNA and evade restriction by the host's innate immune system, preventing it from replicating. In this work, a new series of antiviral compounds that are easy and reproducible to prepare were designed and synthesized. They were endowed with antiviral activity on ZIKAV-infected cells and the most active of them were screened for their absorption, distribution, metabolism, and excretion (ADME) properties in vitro. In the second part of this work, a new compound, a potential inhibitor of the enzyme IMPDH, was designed and synthesized: IMPDH plays an important role in antiviral and anticancer processes as it catalyzes the rate-limiting step in the de novo biosynthesis of guanine nucleotides and can therefore be considered a strategic target for the development of novel antiviral compounds. The last part of the thesis explains the work carried out during the stay abroad at RWTH Aachen University, where the synthesis of an S-allenylsulfoximine derivative was studied: thanks to the allenyl group these compounds can be very useful in organic chemistry when it comes to the incorporation of new units and also, thanks to the sulfoximine moiety can also be used in pharmaceutical chemistry by taking advantage of their important properties.
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10

Biswas, S. "Study of antiviral resistance to helicase-primase inhibitors of herpes simplex virus type 1." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.596674.

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The herpes simplex virus (HSV) helicase-primase complex represents a relatively new target for inhibition by non-nucleoside antiviral compounds. A claimed advantage of helicase-primase inhibitors (HPIs) is the reported low frequency of drug-resistance (approx. 10-6) in tissue culture. It was confirmed in this study that one HPI, the thiozoleamide, known as “BAY 57-1293” is superior to the nucleoside analogue acyclovir against HSV-1 in tissue culture. Furthermore, BAY 57-1293 showed more potent therapeutic antiviral activity than the nucleoside analogue prodrug, famciclovir in BALB/c mice, infected with HSV-1. It was observed that drug-resistant variants could be readily selected by culturing HSV-1 in the presence of BAY 57-1293. The different resistant viruses obtained during this study were stable and showed resistance to BAY 57-1293 varying from approx. 15-fold to >5,000-fold. Several viruses were sequenced to define the genetic lesions. The putative resistance mutations all mapped to either the HSV-1 UL5 helicase or UL52 primase protein. A marker-transfer strategy was established to confirm the role of particular amino acid substitutions in drug-resistance and their effects on other biological properties. Two generally-defined BAY 57-1293 resistant mutants were characterized for cross-resistance to an alternative HPI (BILS 22 BS); growth properties in tissue culture; and pathogenicity in a murine HSV-1 infection model. It was established from these experiments that single mutations close to a predicted functional domain of the UL5 helicase protein account for co-resistance to both HPI, suggesting that both interact with UL5 helicase. The same drug-resistance mutations were also associated with changes (increase or decrease) to virus growth in tissue culture and pathogenicity. Hypotheses are developed to explain possible differences between HPI concerning their interaction with the viral helicase-primase complex. The studies described in this thesis may have a bearing on the potential for HPI-resistance to subvert effective therapy.
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Книги з теми "Antiviral inhibitors"

1

March, Darren. Designing new antiviral drugs for AIDS: HIV-1 protease and its inhibitors. Austin: R.G. Landes, 1996.

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2

American Society for Microbiology. Eastern Pennsylvania Branch and Eastern Pennsylvania Branch of the American Society for Microbiology Symposium of Innovations in Antiviral Development and the Detection of Virus Infections (1990 : Philadelphia, Pa.), eds. Innovations in antiviral development and the detection of virus infections. New York: Plenum Press, 1992.

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3

HIV-1 integrase: Mechanism and inhibitor design. Hoboken, N.J: Wiley, 2011.

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4

Esté, José Andrés. Mode of action and development of resistance to human immunodeficiency virus inhibitors that are targeted at early stages of infection. Leuven, Belgium: Leuven University Press, 1999.

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5

RNA interference and viruses: Current innovations and future trends. Norfolk, UK: Caister Academic Press, 2010.

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6

Martínez, Miguel Angel. RNA interference and viruses: Current innovations and future trends. Norfolk, UK: Caister Academic Press, 2010.

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7

Hans-Georg, Kräusslich, Oroszlan Stephen, Wimmer Eckard, and Cold Spring Harbor Laboratory, eds. Viral proteinases as targets for chemotherapy. Cold Spring Harbor, N.Y: Cold Spring Harbor Laboratory Press, 1989.

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8

Bilimoria, Darius M. Studies involving measles virus receptor interaction and inhibitors of virus mediated membrane fusion (a prelude to a small animal model and antiviral agents directed). Ottawa: National Library of Canada, 1998.

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9

Lendeckel, Uwe, and Nigel M. Hooper, eds. Viral Proteases and Antiviral Protease Inhibitor Therapy. Dordrecht: Springer Netherlands, 2009. http://dx.doi.org/10.1007/978-90-481-2348-3.

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10

H, Wagman Gerald, and Cooper Raymond, eds. Natural products isolation: Separation methods for antimicrobials, antivirals, and enzyme inhibitors. Amsterdam: Elsevier, 1989.

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Частини книг з теми "Antiviral inhibitors"

1

Anderson, Jeffrey, Celia Schiffer, Sook-Kyung Lee, and Ronald Swanstrom. "Viral Protease Inhibitors." In Antiviral Strategies, 85–110. Berlin, Heidelberg: Springer Berlin Heidelberg, 2009. http://dx.doi.org/10.1007/978-3-540-79086-0_4.

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2

Vuagniaux, Grégoire, Arnaud Hamel, Rafael Crabbé, Hervé C. Porchet, and Jean-Maurice Dumont. "Cyclophilin Inhibitors." In Antiviral Drug Strategies, 147–80. Weinheim, Germany: Wiley-VCH Verlag GmbH & Co. KGaA, 2011. http://dx.doi.org/10.1002/9783527635955.ch7.

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3

Wong-Staal, Flossie, Guohong Liu, and Jeffrey McKelvy. "HCV Viral Entry Inhibitors." In Antiviral Drugs, 329–37. Hoboken, NJ, USA: John Wiley & Sons, Inc., 2011. http://dx.doi.org/10.1002/9780470929353.ch23.

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4

Coen, Donald M. "Antiherpesviral DNA Polymerase Inhibitors." In Antiviral Research, 1–18. Washington, DC, USA: ASM Press, 2014. http://dx.doi.org/10.1128/9781555815493.ch1.

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5

Roberts, Noel A. "Anti-influenza drugs and neuraminidase inhibitors." In Antiviral Agents, 35–77. Basel: Birkhäuser Basel, 2001. http://dx.doi.org/10.1007/978-3-0348-7784-8_2.

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6

Baba, Masanori. "Entry Inhibitors of Human Immunodeficiency Virus." In Antiviral Research, 19–32. Washington, DC, USA: ASM Press, 2014. http://dx.doi.org/10.1128/9781555815493.ch2.

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7

Crowe, Suzanne. "New Reverse Transcriptase Inhibitors." In Antiviral Chemotherapy 5, 183–97. Boston, MA: Springer US, 1999. http://dx.doi.org/10.1007/978-1-4615-4743-3_18.

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8

Ren, Shijun, and Eric J. Lien. "Development of HIV protease inhibitors: A survey." In Antiviral Agents, 1–34. Basel: Birkhäuser Basel, 2001. http://dx.doi.org/10.1007/978-3-0348-7784-8_1.

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9

Martinez-Cajas, Jorge L., and Mark A. Wainberg. "Inhibitors of the Human Immunodeficiency Virus Protease." In Antiviral Research, 113–35. Washington, DC, USA: ASM Press, 2014. http://dx.doi.org/10.1128/9781555815493.ch7.

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10

Zimmermann, H., G. Hewlett, and H. Rübsamen-Waigmann. "Other Inhibitors of Viral Enzymes and Functions." In Antiviral Strategies, 155–76. Berlin, Heidelberg: Springer Berlin Heidelberg, 2009. http://dx.doi.org/10.1007/978-3-540-79086-0_6.

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Тези доповідей конференцій з теми "Antiviral inhibitors"

1

"Application of 3D image analysis to facilitate the identification of antiviral inhibitors." In Microscience Microscopy Congress 2023 incorporating EMAG 2023. Royal Microscopical Society, 2023. http://dx.doi.org/10.22443/rms.mmc2023.189.

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2

Fernández, C., A. Cunha, and M. Alves. "NARMA-L2-based Antiviral Therapy for Infected CD4+ T Cells in a Nonlinear Model for HIV Dynamics: Protease Inhibitors-based Approach." In 12th International Conference on Agents and Artificial Intelligence. SCITEPRESS - Science and Technology Publications, 2020. http://dx.doi.org/10.5220/0008980606750683.

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3

PEÑA, CESAR, Amanda Briena Batista Flores da Cunha, and Maise Araujo Alves. "NARMA-L2-based nonlinear model for HIV dynamics: behavior of infected/uninfected CD4+ T cells for antiviral therapy based on protease inhibitors." In ANAIS DO 14º SIMPóSIO BRASILEIRO DE AUTOMAçãO INTELIGENTE. Galoa, 2019. http://dx.doi.org/10.17648/sbai-2019-112481.

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4

Solis-Calero, C., PA Morais, FF Maia Jr, VN Freire, and HF Carvalho. "Explaining SARS-CoV-2 3CL Mpro binding to peptidyl Michael acceptor and a ketone-based inhibitors using Molecular fractionation with conjugate caps method." In VIII Simpósio de Estrutura Eletrônica e Dinâmica Molecular. Universidade de Brasília, 2020. http://dx.doi.org/10.21826/viiiseedmol2020185.

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The main protease SARS-CoV-2 3CL Mpro (3CL-Mpro) is an attractive target for developing antiviral inhibitors due to its essential role in processing the polyproteins translated from viral coronavirus RNA. In this work, it was obtained non-covalent complexes of this protease with two distinct ligands, a peptidyl Michael acceptor (N3) and a ketone-based compound (V2M). The complexes were modeled from processed crystallographic data (PDB id: 6LU7 and 6XHM respectively) using combined quantum mechanics/molecular mechanics (QM/MM) calculations. The QM region was treated at the PBE-def2-SV(P) level, while the Amber-ff19SB force field was used to describe the MM region. The obtained models were used to perform calculations for describing the protease/ligand binding, based in the framework of the Density Functional Theory (DFT) and within the Molecular Fractionation with Conjugated Caps (MFCC) scheme. Our results have shown values for the total interaction energies of -111.84 and -111.64 kcal mol-1 having as ligands a N3 and V2M, respectively. Most importantly, it was possible to assess the relative individual amino acid energy contribution for the binding of both ligands considering residues around them up to 10 Å of radial distance. Residues Gln189, Met165, Glu166, His164, and Asn142 were identified as main interacting amino acid residues for both complexes, being their negative interaction energy contributions higher than -5.0 kcal mol-1. In the case of 3CL-Mpro/ V2M complex, we should add His41, Ser144, and Cys145 as main contributing residues. Our data also have shown that interactions of type π-amide, π-alkyl and alkyl-alkyl and carbon hydrogen bonds should be also considered in order to explain the binding of 3CL-Mpro with the selected inhibitors. Our results also determined that the carbonyl-L-leucinamide scaffold of both inhibitors is its main determinant of binding with a contribution to the energy of interaction of 54.51 and 50.69 kcal mol-1 for N3 and V2M, respectively.
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5

Griego, Anastacia M., Pamela Barraza, Chelin Hu, Agnieszka Dziduszko, Brianna K. Crowley, Helen J. Hathaway, Julie E. Bauman, and Michelle A. Ozbun. "Abstract 3176: The EGFR pathway as the Achilles’ heel for human papillomavirus-induced tumors: EGFR/MAPK pathway inhibitors exhibit antiviral activities and limit tumor growthin vivo." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-3176.

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6

Ay, Emrah, and Nizami Duran. "Synergistic Efficacy of Eucalyptol with Acyclovir against HSV-2." In The 9th International Conference on Advanced Materials and Systems. INCDTP - Leather and Footwear Research Institute (ICPI), Bucharest, Romania, 2022. http://dx.doi.org/10.24264/icams-2022.iii.3.

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The increasing drug resistance in herpes viruses in recent years brings with it new treatment approaches. In recent years, it has been tried to overcome drug resistance, especially with the use of herbal products in combination with existing drugs. In this study, we aimed to investigate the effectiveness of eucalyptol in combination with acyclovir. A Vero cell line was used for toxicity tests and viral culture isolation studies in the study. The non-toxic concentrations of eucalyptol and acyclovir were determined by the MTT method. Antiviral efficacy studies were performed within non-toxic concentrations. Antiviral activity was determined by calculating the IC50 values of the compounds against HSV-2. In addition, it was evaluated by the RT-PCR method. The 50% inhibitory concentration (IC50) and Fractional inhibitory concentration (FIC) index values determined during 24 hours and 48 hours of action showed that Eucalyptol exhibited a potent activity. This efficacy was found to be stronger when used in combination with acyclovir. These results show that the combination of Eucalyptol and acyclovir may be beneficial against resistant HSV infections. We suggest that the results of these studies, which are planned as in-vitro, be supported by in-vivo studies.
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7

Shahab, S. N., and E. N. Vasyukevich. "TRIAZAVIRIN AS A POTENTIAL PROTEASE M INHIBITOR OF CORONOVIRUS 2019-nCoV." In SAKHAROV READINGS 2021: ENVIRONMENTAL PROBLEMS OF THE XXI CENTURY. International Sakharov Environmental Institute, 2021. http://dx.doi.org/10.46646/sakh-2021-1-371-374.

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Triazavirin is a synthesized antiviral drug. It is being investigated for potential use against the 2019-nCoV coronavirus. In this study, the molecular structure of this molecule was investigated using the density functional theory (DFT/B3LYP/MidiX) in the gas phase. Molecular HOMO-LUMO orbitals, excitation energies, and oscillatory forces of the compound under study are also calculated and presented. The interaction of the Triazavirin compound with the Coronavirus was carried out by molecular docking.
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Bartlett, Nathan W., Louise Slater, Gaetano Caramori, Simon Message, Sebastian L. Johnston, and Michael R. Edwards. "Reduced NF-ºB P65 Expression Inhibits Rhinovirus-Induced Inflammation Without Compromising Antiviral Immunity." In American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California. American Thoracic Society, 2012. http://dx.doi.org/10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a3875.

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Xu, F., W. Ouyang, J. Xia, L. Yang, and H. Zhou. "NMI Inhibits Antiviral Immunity by Polyubiquitination and Degradation of IRF3 and IRF7 Through TRIM21." In American Thoracic Society 2020 International Conference, May 15-20, 2020 - Philadelphia, PA. American Thoracic Society, 2020. http://dx.doi.org/10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a3975.

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Nedeljković, Nikola V., Vladimir D. Dobričić, Marina Ž. Mijajlović, Gordana P. Radić, Miloš V. Nikolić, Ana S. Stanković, and Zorica B. Vujić. "„IN SILICO“ PREDICTION OF PHARMACOKINETIC PROPERTIES AND DRUGLIKENESS OF NOVEL THIOUREA DERIVATIVES OF NAPROXEN." In 1st INTERNATIONAL Conference on Chemo and BioInformatics. Institute for Information Technologies, University of Kragujevac, 2021. http://dx.doi.org/10.46793/iccbi21.371n.

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Masking the carboxyl group of naproxen with other functional groups may be a promising strategy to decrease its gastrointestinal toxicity. Thiourea moiety has been described as an important pharmacophore in a variety of pharmacologically active compounds, including anti-inflammatory, antiviral, anticancer, hypoglycemic and antimicrobial agents. Our research group has previously designed twenty novel thiourea derivatives of naproxen, containing amino acids (glycine, L-alanine, β-alanine, L-valine and L-phenylalanine – compounds 1,2,3,4 and 5, respectively), their methyl (6–10) and ethyl esters (11–15), as well as aromatic amines (16–20). Pharmacokinetic properties and druglikeness of these compounds were predicted using SwissADME web tool (http://www.swissadme.ch/). Predicted pharmacokinetic properties include potential for gastrointestinal absorption, blood-brain barrier permeability, skin permeability, transport mediated by P-glycoproteins and enzyme inhibitory potential. Druglikeness was evaluated using Lipinski’s, Ghose’s, Veber’s, Egan’s and Muegge’s rules, as well as on the basis of bioavailability score. All tested compounds had high-predicted gastrointestinal absorption and low blood-brain barrier permeability. Also, derivatives 2, 4, 7, 9, 10, 12, 14, 15 and 18 were predicted to be substrates for P-glycoprotein. Derivatives with aromatic amines (16–20) showed inhibitory potential against all tested CYP isoforms. Derivative 19 had the highest, while derivative 13 demonstrated the lowest predicted skin permeability. Finally, derivatives 1–12, except 5 and 10, have druglike structures, since they obey to all imposed rules.
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Звіти організацій з теми "Antiviral inhibitors"

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Edmundson, Scott, Michael Huesemann, Sherry Cady, Li-Jung Kuo, Brady Anderson, and Daman Reynolds. VITAL- Viral InhibiTors from ALgae: Generating Extracts for Antiviral Activity Assays. Office of Scientific and Technical Information (OSTI), October 2020. http://dx.doi.org/10.2172/1776864.

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Loebenstein, Gad, M. Chessin, and Abed Gera. Resistance Mechanisms to Viruses in Plants Associated with Antiviral Substances (Inhibitors of Virus Replication). United States Department of Agriculture, March 1987. http://dx.doi.org/10.32747/1987.7695597.bard.

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3

Chejanovsky, Nor, and Bruce A. Webb. Potentiation of Pest Control by Insect Immunosuppression. United States Department of Agriculture, January 2010. http://dx.doi.org/10.32747/2010.7592113.bard.

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The restricted host range of many baculoviruses, highly pathogenic to Lepidoptera and non-pathogenic to mammals, limits their use to single or few closely related Lepidopteran species and is an obstacle to extending their implementation for pest control. The insect immune response is a major determinant of the ability of an insect pathogen to efficiently multiply and propagate. We have developed an original model system to study the Lepidopteran antiviral immune response based on Spodoptera littoralis resistance to AcMNPV (Autographa californica multiple nucleopolyhedrovirus) infection and the fascinating immunosuppressive activity of polydnaviruses .Our aim is to elucidate the mechanisms through which the immunosuppressive insect polydnaviruses promote replication of pathogenic baculoviruses in lepidopteran hosts that are mildly or non-permissive to virus- replication. In this study we : 1- Assessed the extent to which and the mechanisms whereby the immunosuppressive Campoletis sonorensis polydnavirus (CsV) or its genes enhanced replication of a well-characterized pathogenic baculovirus AcMNPV, in polydnavirus-immunosuppressedH. zea and S. littoralis insects and S. littoralis cells, hosts that are mildly or non-permissive to AcMNPV. 2- Identified CsV genes involved in the above immunosuppression (e.g. inhibiting cellular encapsulation and disrupting humoral immunity). We showed that: 1. S. littoralis larvae mount an immune response against a baculovirus infection. 2. Immunosuppression of an insect pest improves the ability of a viral pathogen, the baculovirus AcMNPV, to infect the pest. 3. For the first time two PDV-specific genes of the vankyrin and cystein rich-motif families involved in immunosuppression of the host, namely Pvank1 and Hv1.1 respectively, enhanced the efficacy of an insect pathogen toward a semipermissive pest. 4. Pvank1 inhibits apoptosis of Spodopteran cells elucidating one functional aspect of PDVvankyrins. 5. That Pvank-1 and Hv1.1 do not show cooperative effect in S. littoralis when co-expressed during AcMNPV infection. Our results pave the way to developing novel means for pest control, including baculoviruses, that rely upon suppressing host immune systems by strategically weakening insect defenses to improve pathogen (i.e. biocontrol agent) infection and virulence. Also, we expect that the above result will help to develop systems for enhanced insect control that may ultimately help to reduce transmission of insect vectored diseases of humans, animals and plants as well as provide mechanisms for suppression of insect populations that damage crop plants by direct feeding.
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Lapidot, Moshe, and Vitaly Citovsky. molecular mechanism for the Tomato yellow leaf curl virus resistance at the ty-5 locus. United States Department of Agriculture, January 2016. http://dx.doi.org/10.32747/2016.7604274.bard.

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Tomato yellow leaf curl virus (TYLCV) is a major pathogen of tomato that causes extensive crop loss worldwide, including the US and Israel. Genetic resistance in the host plant is considered highly effective in the defense against viral infection in the field. Thus, the best way to reduce yield losses due to TYLCV is by breeding tomatoes resistant or tolerant to the virus. To date, only six major TYLCV-resistance loci, termed Ty-1 to Ty-6, have been characterized and mapped to the tomato genome. Among tomato TYLCV-resistant lines containing these loci, we have identified a major recessive quantitative trait locus (QTL) that was mapped to chromosome 4 and designated ty-5. Recently, we identified the gene responsible for the TYLCV resistance at the ty-5 locus as the tomato homolog of the gene encoding messenger RNA surveillance factor Pelota (Pelo). A single amino acid change in the protein is responsible for the resistant phenotype. Pelo is known to participate in the ribosome-recycling phase of protein biosynthesis. Our hypothesis was that the resistant allele of Pelo is a “loss-of-function” mutant, and inhibits or slows-down ribosome recycling. This will negatively affect viral (as well as host-plant) protein synthesis, which may result in slower infection progression. Hence we have proposed the following research objectives: Aim 1: The effect of Pelota on translation of TYLCV proteins: The goal of this objective is to test the effect Pelota may or may not have upon translation of TYLCV proteins following infection of a resistant host. Aim 2: Identify and characterize Pelota cellular localization and interaction with TYLCV proteins: The goal of this objective is to characterize the cellular localization of both Pelota alleles, the TYLCV-resistant and the susceptible allele, to see whether this localization changes following TYLCV infection, and to find out which TYLCV protein interacts with Pelota. Our results demonstrate that upon TYLCV-infection the resistant allele of pelota has a negative effect on viral replication and RNA transcription. It is also shown that pelota interacts with the viral C1 protein, which is the only viral protein essential for TYLCV replication. Following subcellular localization of C1 and Pelota it was found that both protein localize to the same subcellular compartments. This research is innovative and potentially transformative because the role of Peloin plant virus resistance is novel, and understanding its mechanism will lay the foundation for designing new antiviral protection strategies that target translation of viral proteins. BARD Report - Project 4953 Page 2
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Gafni, Yedidya, Moshe Lapidot, and Vitaly Citovsky. Dual role of the TYLCV protein V2 in suppressing the host plant defense. United States Department of Agriculture, January 2013. http://dx.doi.org/10.32747/2013.7597935.bard.

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TYLCV-Is is a major tomato pathogen, causing extensive crop losses in Israel and the U.S. We have identified a TYLCV-Is protein, V2, which acts as a suppressor of RNA silencing. Intriguingly, the counter-defense function of V2 may not be limited to silencing suppression. Our recent data suggest that V2 interacts with the tomato CYP1 protease. CYP1 belongs to the family of papain-like cysteine proteases which participate in programmed cell death (PCD) involved in plant defense against pathogens. Based on these data we proposed a model for dual action of V2 in suppressing the host antiviral defense: V2 targets SGS3 for degradation and V2 inhibits CYP1 activity. To study this we proposed to tackle three specific objectives. I. Characterize the role of V2 in SGS3 proteasomal degradation ubiquitination, II. Study the effects of V2 on CYP1 maturation, enzymatic activity, and accumulation and, III. Analyze the effects of the CYP1-V2 interaction on TYLCV-Is infection. Here we describe results from our study that support our hypothesis: the involvement of the host's innate immune system—in this case, PCD—in plant defense against TYLCV-Is. Also, we use TYLCV-Is to discover the molecular pathway(s) by which this plant virus counters this defense. Towards the end of our study we discovered an interesting involvement of the C2 protein encoded by TYLCV-Is in inducing Hypersensitive Response in N. benthamianaplants which is not the case when the whole viral genome is introduced. This might lead to a better understanding of the multiple processes involved in the way TYLCV is overcoming the defense mechanisms of the host plant cell. In a parallel research supporting the main goal described, we also investigated Agrobacteriumtumefaciens-encoded F-box protein VirF. It has been proposed that VirF targets a host protein for the UPS-mediated degradation, very much the way TYLCV V2 does. In our study, we identified one such interactor, an Arabidopsistrihelix-domain transcription factor VFP3, and further show that its very close homolog VFP5 also interacted with VirF. Interestingly, interactions of VirF with either VFP3 or VFP5 did not activate the host UPS, suggesting that VirF might play other UPS-independent roles in bacterial infection. Another target for VirF is VFP4, a transcription factor that both VirF and its plant functional homolog VBF target to degradation by UPS. Using RNA-seqtranscriptome analysis we showed that VFP4 regulates numerous plant genes involved in disease response, including responses to viral and bacterial infections. Detailed analyses of some of these genes indicated their involvement in plant protection against Agrobacterium infection. Thus, Agrobacterium may facilitate its infection by utilizing the host cell UPS to destabilize transcriptional regulators of the host disease response machinery that limits the infection.
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