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Abele, Gunnar. "Anti varicella-zoster activity of 2HM-HBG, a new acyclic guanosin analog." Stockholm : Kongl. Carolinska Medico Chirurgiska Institutet, 1988. http://catalog.hathitrust.org/api/volumes/oclc/19412466.html.
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Jornada, Daniela Hartmann [UNESP]. "Síntese e avaliação biológica de bioisósteros de nitrofural ativos contra Leishmania amazonensis." Universidade Estadual Paulista (UNESP), 2015. http://hdl.handle.net/11449/121927.
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A leishmaniose tegumentar possui ampla distribuição mundial, segundo dados da Organização Mundial da Saúde (OMS) e estima-se que haja o surgimento de 500 mil a um milhão de casos por ano. Segundo dados do Departamento de Informática do Sistema Único de Saúde (DATASUS), no ano de 2005 registraram-se mais de 180 milhões de casos de leishmaniose tegumentar no Brasil. Apesar da existência de tratamentos disponíveis, a cura da leishmaniose é um processo complexo, em virtude das dificuldades na administração dos fármacos injetáveis, dos inúmeros efeitos adversos e da toxicidade hepática, renal e cardíaca. Dessa forma o desenvolvimento de novos fármacos mais eficazes e menos tóxicos torna-se urgente. O bioisosterismo é uma ferramenta de modificação molecular que visa à obtenção de novos análogos com a mesma atividade biológica. Assim, tem sido utilizado na pesquisa de novos fármacos, buscando a melhoria na eficácia e segurança no tratamento de diversas doenças. O nitrofural (NF), 5-nitro-2-furaldeído semicarbazona, é um fármaco utilizado como antimicrobiano de uso tópico em vários tipos de lesões de pele, que apresenta atividade descrita contra formas amastigotas de L. donovani, L. enriettii e L. major. Baseando-se nas diversas atividades do fármaco, o trabalho proposto objetivou a síntese de bioisósteros de nitrofural e avaliação dos compostos quanto à atividade leishmanicida in vitro. Foram sintetizados e caracterizados através de métodos analíticos oito compostos, sendo um inédito. Sete deles foram avaliados quanto à atividade biológica frente às formas amastigotas de L.amazonensis, através do ensaio de MTT (brometo de 3-metil[4,5-dimetiltiazol-2-il]-2,5 difeniltetrazólio). O composto Lapdesf-MetSFS (8) apresentou atividade comparável à da pentamidina, fármaco padrão utilizado na terapêutica.
Cutaneous leishmaniasis is a world widely distributed disease and it is estimated, by the World Health Organization (WHO), the incidence of 500,000 to one million cases per year. According to the Department of the Unified Health System (DATASUS), in 2005 it was registered more than 180 million cases of cutaneous leishmaniasis in Brazil. Although treatments for leishmaniasis are available, it is a complex process, because of difficulties in administration, once the majority of the drugs are injectable, the several numbers of adverse effects, and liver, renal and cardiac toxicity. Due to that, the development of more effective and less toxic drugs becomes urgent. The bioisosterism is a molecular modification strategy that aims to obtain new analogues with the same biological activity. It has been used in the research for new drugs, in order to improve the effectiveness and safety in the treatment of various diseases. The nitrofural (NF) 5-nitro-2-furaldehyde semicarbazone, is a drug used as topical antimicrobial in various types of skin lesions is described which has activity against L. donovani, L. enriettii and L. major amastigote forms. Based on the various drug activities, the proposed work aimed the synthesis of bioisosters of nitrofural and evaluation of compounds for in vitro leishmanicidal activity. Were synthesized and characterized via analytical methods eight compounds, one unpublished. Seven of them were evaluated for biological activity against the amastigotesn forms of L. amazonensis by MTT assay (3-methyl bromide [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide). The Lapdesf-MetSFS (8) compound showed activity comparable to that of pentamidine, standard drug used in therapy.
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Jornada, Daniela Hartmann. "Síntese e avaliação biológica de bioisósteros de nitrofural ativos contra Leishmania amazonensis /." Araraquara, 2015. http://hdl.handle.net/11449/121927.
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Orientador: Chung Man ChinCoorientador: Priscila Longhin Bosquesi
Banca: Eduardo René Pérez González
Banca: Renato Farina Menegon
Resumo: A leishmaniose tegumentar possui ampla distribuição mundial, segundo dados da Organização Mundial da Saúde (OMS) e estima-se que haja o surgimento de 500 mil a um milhão de casos por ano. Segundo dados do Departamento de Informática do Sistema Único de Saúde (DATASUS), no ano de 2005 registraram-se mais de 180 milhões de casos de leishmaniose tegumentar no Brasil. Apesar da existência de tratamentos disponíveis, a cura da leishmaniose é um processo complexo, em virtude das dificuldades na administração dos fármacos injetáveis, dos inúmeros efeitos adversos e da toxicidade hepática, renal e cardíaca. Dessa forma o desenvolvimento de novos fármacos mais eficazes e menos tóxicos torna-se urgente. O bioisosterismo é uma ferramenta de modificação molecular que visa à obtenção de novos análogos com a mesma atividade biológica. Assim, tem sido utilizado na pesquisa de novos fármacos, buscando a melhoria na eficácia e segurança no tratamento de diversas doenças. O nitrofural (NF), 5-nitro-2-furaldeído semicarbazona, é um fármaco utilizado como antimicrobiano de uso tópico em vários tipos de lesões de pele, que apresenta atividade descrita contra formas amastigotas de L. donovani, L. enriettii e L. major. Baseando-se nas diversas atividades do fármaco, o trabalho proposto objetivou a síntese de bioisósteros de nitrofural e avaliação dos compostos quanto à atividade leishmanicida in vitro. Foram sintetizados e caracterizados através de métodos analíticos oito compostos, sendo um inédito. Sete deles foram avaliados quanto à atividade biológica frente às formas amastigotas de L.amazonensis, através do ensaio de MTT (brometo de 3-metil[4,5-dimetiltiazol-2-il]-2,5 difeniltetrazólio). O composto Lapdesf-MetSFS (8) apresentou atividade comparável à da pentamidina, fármaco padrão utilizado na terapêutica.
Abstract: Cutaneous leishmaniasis is a world widely distributed disease and it is estimated, by the World Health Organization (WHO), the incidence of 500,000 to one million cases per year. According to the Department of the Unified Health System (DATASUS), in 2005 it was registered more than 180 million cases of cutaneous leishmaniasis in Brazil. Although treatments for leishmaniasis are available, it is a complex process, because of difficulties in administration, once the majority of the drugs are injectable, the several numbers of adverse effects, and liver, renal and cardiac toxicity. Due to that, the development of more effective and less toxic drugs becomes urgent. The bioisosterism is a molecular modification strategy that aims to obtain new analogues with the same biological activity. It has been used in the research for new drugs, in order to improve the effectiveness and safety in the treatment of various diseases. The nitrofural (NF) 5-nitro-2-furaldehyde semicarbazone, is a drug used as topical antimicrobial in various types of skin lesions is described which has activity against L. donovani, L. enriettii and L. major amastigote forms. Based on the various drug activities, the proposed work aimed the synthesis of bioisosters of nitrofural and evaluation of compounds for in vitro leishmanicidal activity. Were synthesized and characterized via analytical methods eight compounds, one unpublished. Seven of them were evaluated for biological activity against the amastigotesn forms of L. amazonensis by MTT assay (3-methyl bromide [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide). The Lapdesf-MetSFS (8) compound showed activity comparable to that of pentamidine, standard drug used in therapy.
Mestre
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Jun, Min Medical Sciences Faculty of Medicine UNSW. "Analysis of human cytomegalovirus susceptibility to novel antiviral agents." Publisher:University of New South Wales. Medical Sciences, 2008. http://handle.unsw.edu.au/1959.4/41443.
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Human cytomegalovirus (CMV) is a significant infectious agent causing disease in immunocompromised HIV-infected patients, transplant recipients, and neonates. The current antiviral therapeutic strategy against CMV is limited in its utility due to the inherent toxicity and lack of bioavailability of currently available anti-CMV agents, ganciclovir (GCV), cidofovir (CDV), and foscarnet (FOS). The development of the prodrug of GCV, valganciclovir (val-GCV), has vastly improved the bioavailability profile of GCV. However, val-GCV demonstrates limited effectiveness against tissue-invasive CMV diseases as side effects involved with traditional intravenously administered GCV such as haematologic and reproductive toxicities remain. In addition, the emergence of antiviral resistant CMV mutant strains due to prolonged treatment with currently available antivirals necessitates the development of novel anti-CMV agents with reduced toxicity and improved bioavailability. In this study, select groups of novel compounds were analysed for their potential for further development as anti-CMV agents. Three groups of compounds were identified based on two screening methods which included the computer simulated screening process of compounds known as in silico screening and the traditional method of random screening. The first group of compounds (CATi) were identified by in silico screening against the CMV DNA polymerase catalytic aspartate triad, resulting in the identification of 31 compounds with the potential for inhibitory activity against CMV. The second group of compounds (PRO-i) were identified through in silico screening against the CMV protease, identifying a total of 18 lead compounds exhibiting structural complementarity with CMV protease. The third and final group of compounds (TPEX) were identified through random screening and consisted of plant extracts purified from tropical plants. All three compounds were initially screened for cytotoxicity against human fibroblasts. Plaque reduction assays were performed using compounds with acceptable levels of cytotoxicity to determine the ability of the compounds to inhibit the replication of the laboratory antiviral sensitive CMV strain, Towne. Two of the PRO-i compounds demonstrated good antiviral activity against CMV. Eleven percent (2/18) of the PRO-i compounds inhibited CMV replication, with PRO-i-43 and PRO-i??-44 displaying mean 50% inhibitory concentrations (IC50) of 4.8 ?? 1.2 ??M and 8.04 ??M, respectively. PRO-i-43 and PRO-i-44 are thus good candidates for further development as novel antiviral agents against CMV. The majority of CATi and TPEX compounds displayed significant cytotoxicity against human fibroblasts and compounds with acceptable levels of cytotoxicities did not significantly inhibit CMV replication. However, the identification of compounds with low cytotoxicities provides a good foundation for further development of novel anti-CMV agents with superior antiviral activity. In silico screening against three-dimensional viral protein models is a useful strategy for the identification of novel antiviral agents with the potential for inhibitory activity against CMV. Structural modification to produce potent derivatives of the identified anti-CMV compounds (PRO-i-43 and PRO-i-44) is a good option for the further development of novel antiviral agents against CMV. Such further examination of the identified compounds with anti-CMV activity is required to investigate their activity against not only antiviral sensitive CMV strains but also resistant CMV strains. Further investigations will yield new insights into their target, allowing further identification of compounds with potential anti-CMV activity with pharmaceutical application.
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Shulyak, Tetyana S. "Exploring sinefungin analogs as potential antiviral agents." Auburn, Ala., 2005. http://repo.lib.auburn.edu/2005%20Summer/doctoral/SHULYAK_TETYANA_14.pdf.
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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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Naylor, M. A. "Heterocyclic pyrophosphate analogues as potential antiviral agents." Thesis, University of Warwick, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.373052.
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Clifton, Heather A. "Computational antiviral drug design." Muncie, Ind. : Ball State University, 2009. http://cardinalscholar.bsu.edu/645.
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Hagos, Asmerom M. "Tricyclic purine analogues as antiparasitic and antiviral agents." Diss., Available online, Georgia Institute of Technology, 2004:, 2003. http://etd.gatech.edu/theses/available/etd-03292004-141831/unrestricted/hagos%5Fasmerom%5Fm%5F200312%5Fphd.pdf.
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Trefry, John Christopher. "The Development of Silver Nanoparticles as Antiviral Agents." Wright State University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=wright1307721406.
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Nobre, Rita Luisa Valentim de Avelar. "Viral interferon antagonists and antiviral drugs /." St Andrews, 2009. http://hdl.handle.net/10023/818.
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Popescu, Anne. "Racemic carbocyclic nucleosides and their anti-viral activity." Lund : Lund University Chemical Center, 1995. http://books.google.com/books?id=5vhqAAAAMAAJ.
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Woodhouse, Gillian Erica. "The effects of viral inactivation agents on the activities of monoclonal antibodies." Thesis, The University of Sydney, 1993. https://hdl.handle.net/2123/26592.
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The aim of this thesis was to determine whether or not two viral inactivation methods which had been developed for use with blood products, affected either antigen binding or secondary biological functions of two selected model antibody molecules. It was postulated that at least one of the viral inactivants, BPL, would affect the functional integrity of antibody molecules since it is reactive with proteins and has been used to block the complement-fixing properties of gamma-globulins.
As one of the most important functions of antibodies is opsonization, which occurs through binding of the F region to the Fe receptors in the cell membrane and binds complement, an in vitro model for this process such as hemolysis, serves ac a useful assay. Because haemagglutination and hemolysis serve as useful models for determining the functional integrity of antibodies in situ, these were the initial assays chosen to detect whether either of the two chemical viral inactivants, PL and TNBP, had a detrimental effect on the variable (antigen-binding) region or Fc region (effector function) of the two model monoclonal antibodies. However, the results from these assays were not clear cut and difficult to interpret due to both the inherent difficulty in reading the assays, i.e. the absence of an electronic component to provide sensitivity in measurement and the sensitivity of the antibody reaction to its physicochemical environment. The ELISA provides a useful comparison to haemagglutination and haemolysis assays as it overcomes these limitations. ELISAs can be used as a comparison but not a substitute for haemagglutination and haemolysis since the proteins are fixed onto a solid substrate so their mobility is restricted and the Fe is not assessed for its effector functions.
It is therefore proposed that a series of assays is required to determine the functionality of the variable and F regions of antibodies. In the future NMR will have a large part to play in the analysis of antibody purity but so far its use is limited to observing the conformation of variable domains. For the present, the assays chosen for this thesis were seen as the appropriate option to obtain data of greatest significance.
By ELISA it has been determined that the viral inactivation treatment using BPL with an IgM monoclonal antibody preparation resulted in a 25 % reduction in antigen-binding activity of the variable region, i.e. a 25 % reduction of antigen-antibody complex was detected. The results obtained from haemagglutination and haemolysis assays were less clear cut for reasons discussed previously. Initially, a reduction in titre for both haemagglutination and haemolysis was observed so that, as with the ELISA, a reduction in antigen binding activity followed treatment with BPL. Because an antigen-antibody complex has a greater affinity for an Fc receptor than an unbound antibody, the reduction in haemolytic activity does necessarily indicate a chemical modification of the Fc region. Subsequently, when the assays were repeated in the presence of 5 % BSA, a reduction in neither the haemagglutination nor the haemolytic titres were observed. It is conceivable that while the affinity constant and hence detectability was increased using BSA, the precision of the measurement was reduced to such a degree that the differences in avidity of the antibody molecules could not be detected.
No significant alteration in overall biological activity, as measured by ELISA, haemagglutination or haemolysis resulted when the same IgM monoclonal antibody preparation was subjected to the viral inactivation procedure using TNBP. No significant alteration in the antigen-binding activity, measured by haemagglutination resulted when a model human IgG1 monoclonal antibody preparation was subjected to the viral inactivation procedures using either TNBP or BPL; however, this assay was carried out in the presence of 5 % BSA and, as been concluded from the previous experiments, further assays may be required to detect an alteration.
It may be concluded that although the use of EPL as an viral inactivant is the only chemical treatment method available to inactivate all viruses for which it has been tested, it significantly reduces the antigen-binding ability of a mouse IgM molecule; also, it is likely that /LPL modifies the Fc region to reduce its functional integrity (115). Procedures such as filtration or lyophilisation have advantages in that they have been demonstrated to yield a safe product; however, filters available cannot remove very small viruses and the use of lyophilisation for inactivation has not been substantially investigated.
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Rodrigues, Ana Mara Lopes. "Interferon, virus vaccines and antiviral drugs /." St Andrews, 2007. http://hdl.handle.net/10023/413.
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Harrison, M. "Synthesis of acyclic c-nucleosides as potential antiviral agents." Thesis, Heriot-Watt University, 1988. http://hdl.handle.net/10399/1004.
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Bouali, Abderrahime. "#beta#-D-ketofuranosyl purine nucleosides as potential antiviral agents." Thesis, University of Lincoln, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.359008.
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Earley, Daniel F. "Development of Novel Heparan Sulfate Analogues as Antiviral Agents." Thesis, Griffith University, 2020. http://hdl.handle.net/10072/392048.
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Heparan sulfate (HS) is a large, poly-anionic, linear polysaccharide that is made up of repeating disaccharide units of alternating glucosamine and gluco or ido uronic acid residues, and that features distinct patters of O- and N-sulfation. In mammalian biology, HS is the most prominent glycosaminoglycan (GAG) and in the form of heparan sulfate proteoglycans (HSPGs) is a major constituent of the extracellular matrix. As such, HSPGs are inherently involved in an enormous diversity of biological functions. Extracellular HSPGs are almost ubiquitously expressed in mammalian systems and therefore many viral, bacterial, and parasitic human pathogens initiate infection through recognition of and attachment to HSPGs on the surface of host cells.
In microbial pathogenesis, HSPGs primarily function as initial, low affinity co-receptors that provide a scaffold to mediate the interaction of microbes with the host cell. Concentration of the pathogen at the cell surface, then allows enhanced binding to specific secondary receptors that facilitate host cell entry. Many viruses adopt HSPGs as cellular receptors to facilitate attachment and entry, including enteroviruses (e.g. enterovirus A71, EV71) and pneumoviruses (human respiratory syncytial virus, hRSV, and human metapneumovirus, hMPV). EV71 is a major cause of hand, foot, and mouth disease, and hMPV is a leading cause of acute respiratory tract infections in children. It has been shown that poly-anionic carbohydrate-based agents (natural polysulfated oligosaccharides, as well as the highly sulfated oligomannoside HS mimetic PI-88) show antiviral activity. However, despite the extensive work carried out there remains no specific antivirals available for the treatment of EV71 and hMPV infections. Due to the increasing understanding of how HSPGs are involved in viral pathogenesis, we sought to investigate how the interactions of HS GAGs could be exploited for drug discovery purposes against a number of viral targets including EV71 and hMPV.
Chapter 2 presents the investigation of HS disaccharide fragments and mimetics as inhibitors of EV71 in vitro infection. To begin the study, a series of HS disaccharide fragments were synthesised that possessed varied sulfation patterns to broadly represent the chemical diversity of HS disaccharides. Utilising saturation transfer difference (STD) NMR, and screening against EV71 cell infection, we were able to identify an increase in EV71 binding affinity for fragments that feature higher levels of sulfation. Armed with this information, we then rationally designed and synthesised a series of highly sulfated HS disaccharide mimetics that feature additional sulfation to those of naturally occurring HS disaccharide fragments. Furthermore, we were able to utilise the structurally simple D-maltose, in the place of natural HS disaccharide scaffolds, without any significant loss of potency. An aryl aglycone was found to increase antiviral potency over the simple methyl glycoside, leading to synthesis of a series b-maltosyl 4-aryl-1,2,3-triazole derivatives. The most active compounds, which incorporate a sulfate group on the aryl ring of the aglycone, provide sub-micromolar inhibition of EV71 infection across a range of different cell lines. These functionalised and more densely sulfated HS mimetic disaccharides were found to significantly more potent than the known inhibitors HS and heparin. Data from functional biological assays, including assessment of the effect of compound addition at different stages of viral infection indicated that the compounds were most effective before, or as the virus bound to the cell, and that the observed binding events occur specifically at the viral surface. We therefore proposed that the sulfated HS mimetic disaccharides interfere with virus-cell interactions by acting as decoy receptors to block EV71 infection. In addition, the compounds were assessed for their anticoagulant activity, and importantly unlike HS and heparin, did not affect plasma clotting time even at very high concentrations. The compounds described in this chapter demonstrate potent inhibition of EV71 infection and that poly-sulfated HS mimetic disaccharides can serve as scaffolds for the development of novel EV71 inhibitors.
Chapter 3 presents the inhibitory activity of poly-sulfated HS mimetic disaccharides against an alternative HS-recognising viral target, hMPV. HSPGs have been identified as an essential attachment factor for initiation of hMPV infection. Targeting this initial stage of cell infection, we investigated the effect of poly-sulfation of small-molecule, carbohydrate-based compounds on inhibition if hMPV in vitro infection. In addition to the series of sulfated disaccharides described in Chapter 2, an alternative scaffold in N-acetylneuraminic acid (Neu5Ac) was also explored. The poly-sulfated disaccharides and Neu5Ac a-glycoside derivatives were evaluated against hMPV in vitro infection of rhesus monkey kidney epithelial (LLC-MK2) cells. The poly-sulfated HS mimetic disaccharides (maltosides), and in particular those that bear a negatively charged aglycone unit, were found to produce inhibition of hMPV in vitro infection at low micromolar concentrations, demonstrating efficient antiviral activity and an improvement over the known small-molecule hMPV inhibitors ribavirin and suramin. This proof of concept study demonstrated that sulfated maltosides and Neu5Ac derivatives can serve as new templates for the development of novel inhibitors of hMPV infection.
Finally, Chapter 4 presents extensive additional work that was carried out for the EV71 project, as well as some preliminary studies against a third viral target, influenza A virus. For the development of EV71 inhibitors, we explored the effects of changing the size of the inhibitor footprint for both HS fragments and mimetics, as well as the use of different linkers between the carbohydrate scaffold and the aglycone. It was found that for HS fragments, a tetrasaccharide is more efficacious than that of a disaccharide. Yet for densely sulfated carbohydrates, the disaccharides were most efficient at blocking EV71 infection. Furthermore, the sulfated hydroxy-phenyl motif, similar in nature to sulfated tyrosines that are found on the side-chains of the EV71 receptor PSGL-1, when bound to sulfated maltosides seemed to endow more effective binding, even compared to display of poly-sulfated maltosyl triazole dimers. This chapter also features an integrated discussion of future research directions and presents the overall conclusions for the body of work described in the thesis.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
Institute for Glycomics
Griffith Health
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Borg, Natalia. "Distribution of antiviral nucleoside analogues to brain and skin /." Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3202-6/.
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Law, Kin Bon. "Mechanistic study of type I ribosome-inactivating protein as anti-influenza and anti-tumour agent." HKBU Institutional Repository, 2000. http://repository.hkbu.edu.hk/etd_ra/253.
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Craven, David A. "Synthesis of hydroxyalkylated pyrrolo- and thienopyrimidines as potential antiviral agents." Thesis, Heriot-Watt University, 1990. http://hdl.handle.net/10399/911.
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Sun, Jian. "Computer-aided drug design for influenza A virus." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B44205156.
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Mak, Ka-ki Peter. "The potential trade-offs between treatment and prophylaxis with antivirals in households during a pandemic." View the Table of Contents & Abstract, 2007. http://sunzi.lib.hku.hk/hkuto/record/B38479631.
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Boisvert, Suzanne 1955. "Preparation of novel heterocyclic-ring analogues of BIOLF-62 : application of 29SI NMR nucleosides and the investigation of 2,4-dinitrobenzenesulfenyl as a protecting group for ribonucleotide synthesis." Thesis, McGill University, 1986. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=75365.
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In light of the remarkable antiviral activity of acyclic nucleoside analogues such as that of BIOLF-62 against the herpes viruses, a number of products in which heterocyclic bases were coupled to the active acyclic sugar moiety were prepared and submitted for biological testing.Various dimethoxytritylated and t -butyldimethylsilylated derivatives of arabinoadenosine were prepared and fully characterised by $ sp1$H and $ sp{13}$C NMR spectroscopy. $ sp{29}$Si INEPT as well as $ sp{29}$Si-$ sp1{ rm H}$ correlated NMR were used to study various t -butyldimethylsilyl and triisopropylsilyl substituted ribonucleosides.
In an effort aimed at the development of new and better nucleoside protecting functions, the 2,4-dinitrobenzenesulfenyl group which is stable to both acidic and basic conditions, was used for $5 sp prime$-hydroxyl protection of ribonucleosides and its compatibility with the phosphodichoridite nucleoside coupling procedure was investigated. The nitrobenzenesulfenyl group was used in conjunction with the dimethoxytrityl group for $2 sp prime$-hydroxyl protection in the synthesis of a UpU dimer. The latter was fully characterised by enzymatic degradation and HPLC analysis of the products.
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Mak, Ka-ki Peter, and 麥家麒. "The potential trade-offs between treatment and prophylaxis with antivirals in households during a pandemic." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B39724517.
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Lau, Yuen-chi Roy. "Response strategies against emergence of antiviral resistance during an influenza pandemic." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B41710666.
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Bianchi, Bianca Real 1987. "Estudo da atividade anti-herpética de isolados de organismos marinhos." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/308719.
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Orientadores: Clarice Weis Arns, Luciana Konecny KohnDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: O vírus herpes simples do tipo 1 (HSV-1), agente etiológico do herpes labial em humanos, é facilmente transmitido e têm o grande problema de causar infecções latentes, sendo que uma vez infectado, o indivíduo passa a ser o portador do vírus por toda a vida. O medicamento mais apropriado contra este tipo de vírus deve ter ação inibitória em qualquer estágio de sua replicação, além de baixa toxicidade, para que as células do hospedeiro não sejam afetadas. Os organismos marinhos representam uma vasta biodiversidade que inclui cerca de 80% de todas as espécies do planeta, o que nos leva a uma grande quantidade de informações que ainda poderão ser descobertas, inclusive acerca de compostos com atividade antiherpética, já que atualmente temos poucos medicamentos disponíveis e nem sempre de total eficácia. Para o estudo com HSV-1 foi escolhida a cepa KOS, por ser resistente ao medicamento considerado mais eficaz para o herpes humano, o aciclovir. Foi utilizada a linhagem celular VERO para o estudo da atividade antiviral de extratos de organismos marinhos. Inicialmente foi realizada uma triagem com 129 extratos. Utilizou-se a concentração de 50?g/ml para todos os extratos, considerando ativos aqueles que apresentaram 97% de inibição do crescimento viral. Dentro dos grupos analisados foram identificados 6 extratos brutos de fungos e 7 extratos brutos de esponjas marinhas como possíveis antivirais. O cálculo do Índice de Seletividade foi realizado para as amostras de fungos Demateaceous (grupo) e Trichoderma sp., apresentando os valores 0,03 e 0,3, com atividade nas fases de adsorção e inativação viral, respectivamente e, para as amostras de esponjas, Monanchora arbuscula e Hemimycale sp., ambas apresentando o valor 0,1, com atividade também nas fases de adsorção e inativação viral, respectivamente
Abstract: Herpes simplex virus type 1 (HSV-1), the etiologic agent of herpes labialis in humans, is transmitted easily and have great problem to cause latent infections, and once infected, the individual becomes the carrier of the virus by life. The most suitable medicament against such virus should have inhibitory action at any stage of its replication as well as low toxicity to the host cells is not impaired. Marine organisms represent a wide biodiversity that includes about 80% of all species on the planet, which leads to a large amount of information that can still be found, including about compounds that may help a possible treatment of symptoms caused by this virus, since currently available medicines have few and not always fully effective. For the study of HSV-1, the KOS strain was chosen because it is resistant to the drug considered most effective for the human herpes, the acyclovir. Was used the cell lines VERO (African Green Monkey - ATCC CCL 81) for the study the antiviral activity of extracts of marine organisms. Initially was realized a screening with 129. We used the concentration of 50?g/ml for all the extracts, whereas those with active 97% inhibition of viral growth. Within the groups analyzed were identified 6 extracts of fungus and 7 crude extracts of marine sponges as possible antiviral. The calculation of the Selectivity Index was conducted for samples of fungi Demateaceous (group) and Trichoderma sp., presenting the values 0.03 and 0.3 with activity phases of adsorption and viral inactivation, respectively, and for samples of sponges, Monanchora arbuscula and Hemimycale sp. both presenting the value 0.1, with activity also in the phases of adsorption and viral inactivation, respectively
Mestrado
Clinica Medica
Mestra em Ciências
27
Clark, Sarah Alexandra. "The synthesis of 2-fluoromethyl nucleosides as potential antiviral agents." Thesis, Queen's University Belfast, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492322.
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Nucleoside analogues are a vital class ofcompounds that are used in the treatment of AIDS and other viral infections. Research into the synthesis of2'-C-fluoromethyl cytosine is described. The key step in the synthesis involves the fluorination ofthe 2-Chydroxymethyl derivative of ribose with Deoxo-Fluoi'lY. The 2-C-hydroxymethyl compound is readily prepared from D-ribose on a multigram scale. Research was carried out into the synthesis of2', 3'-dideoi\.')'-2'-C-fluoromethyl-3'-Chydroxymethyl nucleosides using various different methodologies and a few different starting materials, including D-mannitol and O-benzyl-DL-serine. The key steps consisted ofthe production ofa Z-isomer in a Wittig reaction which could then cyclise to form a butenolide. Once this key component had been formed, a regio- and stereoselective photocatalysed addition ofmethanol was carried out. Supplied by The British Library - 'The world's knowledge'
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McKeen, Catherine M. "Synthesis of acylamino derivatives of acyclonucleosides as potential antiviral agents." Thesis, Heriot-Watt University, 1992. http://hdl.handle.net/10399/1453.
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Meers, Joanne. "The effects of antiviral agents on feline immunodeficiency virus infection." Thesis, Meers, Joanne (1994) The effects of antiviral agents on feline immunodeficiency virus infection. PhD thesis, Murdoch University, 1994. https://researchrepository.murdoch.edu.au/id/eprint/53284/.
Full textAbstract:
Feline immunodeficiency virus (FIV) is a recently discovered lentivirus with many structural and replicative similarities to human immunodeficiency virus (HIV), and has been suggested as a useful animal model for the evaluation of anti-HIV chemotherapy. The successful use of the model is dependent on the development of techniques to accurately measure the response to antiviral treatment in FIV-infected cats.
FIV was isolated by the co-cultivation of peripheral blood mononuclear cells (PBMC) from seropositive cats with PBMC of seronegative donor cats, or with MYA-1 cells (a feline T-lymphoblastoid cell line). Propagation of FIV isolates was unsuccessful in Crandell feline kidney cells, but was successful in PBMC cultures, primary feline thymocytes, and MYA-1 cells.
The biological characteristics of 3 West Australian isolates of FIV were compared. The isolates had similar properties to each other, and to other reported isolates of FIV, including similar cytopathic effect (CPE), electron microscopic appearance, magnesium-dependent reverse transcriptase (RT) activity, FIV p26 core antigen production and the nucleotide sequence of gag and pol genes.
Tetrazolium-based colourimetric assays were used to quantify the CPE of FIV by demonstrating the loss of cell viability in FIV-infected MYA-1 cell cultures. These assays were then used for the titration of FIV, to assess the cytotoxicity of antiviral agents in vitro, and to determine the protection provided by antiviral agents against the CPE of FIV. Five of 6 agents evaluated by these assays provided protection against CPE induced by 2 isolates of FIV. These agents consisted of 4 RT inhibitors (zidovudine, ddC, ddI, foscarnet) and one inhibitor of virus binding/entry (dextran sulphate). A novel agent, acemannan, provided no protection against the CPE of FIV. The inhibition by zidovudine of RT activity and FIV p26 antigen levels in culture supernatant was also demonstrated.
The titre of FIV in PBMC and plasma was determined in 18 experimentally-infected cats and 2 naturally-infected cats, by end-point dilution cultures. The proportion of PBMC containing provirus was determined by polymerase chain reaction (PCR) on serially diluted samples of PBMC from 10 cats. It was demonstrated that following inoculation with virus, the titre of FIV in PBMC increased rapidly to a relatively high level which was then maintained for up to 8 months. In most cats, approximately 1 in 200 PBMC contained virus by 4 weeks post inoculation (p.i.). The results from PCR generally correlated with those from virus isolation, suggesting that the proportion of FIV provirus that is replication defective may be comparatively low. The titre of FIV in plasma peaked at approximately 2 weeks p.i., and then in many cats, declined to undetectable levels. Virus was not isolated from plasma of 2 naturally-infected cats. In some cats, plasma virus titres did not decline by up to 32 weeks p.i., suggesting that there is a variation in the immune response, which enables some, but not all, cats to clear virus from plasma.
The effect of treatment with cyclosporine on the virus titre in cats experimentally infected with FIV was investigated. Treatment began 24 hrs p.i., and continued for 4 weeks. Cyclosporine treatment lowered plasma virus titres at 2 weeks p.i., but at 4 weeks p.i. the plasma virus titre of cyclosporine-treated cats was significantly higher than in untreated cats. This suggested that, initially, the suppression of T-cell activation resulted in the inhibition of viral expression and lower plasma virus titres. However, the broader immunosuppressive effect of treatment eventually dominated the former effect, resulting in an inability to control viral replication and/or clear virus from plasma. Cyclosporine treatment did not influence the titre of FIV in PBMC.
The studies on virus load, combined with the cyclosporine data, suggest that the immune response plays a major role in the control of plasma virus titres in lentiviral infections, but has little influence on the level of cell virus titres.
Treatment of infected cats with zidovudine resulted in significant effects on virus load. Two different dose rates of zidovudine, administered at different times p.i. and with different durations of treatment, were assessed. Zidovudine treatment, with either dose regime, did not prevent establishment of infection with FIV. However, the plasma virus titre of zidovudine- treated cats, using either dose regime, was significantly lower than in untreated cats on at least one sampling occasion. The PBMC virus titre of cats treated with the higher dose of zidovudine was significantly lower than untreated cats at two sampling times. Treatment with the lower dose of zidovudine did not significantly influence PBMC virus titre. This suggested that while the effect of zidovudine on the level of PBMC virus titre may predominantly be the result of the inhibition of viral RT, the effect of zidovudine on plasma virus titres may be the result not only of RT inhibition, but also the result of the suppression of T-cell activation by zidovudine.
This work established methods by which the effect of antiviral or immunomodulating agents on the titres of FIV in PBMC and plasma of infected cats can be investigated and has demonstrated that FIV infection can be used as an effective animal model for the evaluation of antiviral agents against HIV. It has also contributed to the broader investigation of the immunopathogenesis of lentiviral infections.
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Padilla, Marina Aiello 1986. "Atividade antiviral de extratos de plantas do Cerrado contra herpesvírus." [s.n.], 2011. http://repositorio.unicamp.br/jspui/handle/REPOSIP/308716.
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Orientador: Clarice Weis ArnsDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Os herpesvírus são responsáveis por enfermidades importantes em humanos e animais. Em animais, estão associados a doenças que causam grandes perdas econômicas. Em humanos, a gravidade da enfermidade é maior quando os pacientes são imunossuprimidos. Além disso, já existem cepas mutantes resistentes aos medicamentos disponíveis. Visto as dificuldades associadas a prevenção e tratamento das infecções por herpesvírus, a utilização de produtos de plantas como antivirais apresenta - se como alternativa. O Cerrado Brasileiro é um bioma que localiza -se praticamente todo no Brasil e apresenta mais de 10.000 espécies de plantas. Essas plantas podem potencialmente servi r de fonte de compostos farmacologicamente ativos. Assim, o presente trabalho teve como objetivos avaliar a atividade antiviral , atividade virucida e o índice de seletividade (SI) de extratos de plantas do Cerrado contra os herpesvírus suíno tipo 1 (SuHV-1), equinotipo 1 (EHV-1) e vírus do herpes simplex tipo 1 (HSV-1) . Inicialmente, os extratos liofilizados foram submetidos aos testes de citotoxicidade em células MDBK e Vero para determinar a concentração máxima não tóxica (CMNT). Dos extratos, quatro apresentaram as mesmas CMNT's em ambas as linhagens mas, em geral , os extratos foram mais citotóxicos para células Vero. A seguir, com base na CMNT, foram realizados os testes de atividade antiviral para os vírus HSV-1 e EHV-1 em células Vero, e SuHV-1 em MDBK. Os resultados demonstraram que 50% dos extratos apresentaram atividade contra pelo menos um dos herpesvírus estudados, com destaque para as espécies Banisteriopsis variabil is , Byrsonima intermedia e Xylopia aromática que foram ativas contra os t rês herpesvírus, e o extrato da Stryphnodendron adstringens , ativo contra o HSV-1 e SuHV-1. Os extratos que apresentaram atividade antiviral foram então testados quanto a atividade virucida e os resultados submetidos ao cálculo do SI. O extrato foi considerado ativo quando o índice de inibição viral ( IIV) foi maior ou igual a 1,5 ou apresentou PI% (porcentagem de inibição) maior ou igual a 97%. Quanto ao SI, foram considerados ativos os extratos que apresentaram valores iguais ou superiores a 4. A atividade virucida foi observada em 75% dos extratos contra pelo menos um dos herpesvírus testados. As espécies que apresentaram os resultados mais promissores foram: B. variabil is, X. aromática, S. adstringens e B. intermedia. Esta última foi então utilizada em testes adicionais com a variação da concentração, e demonstrou atividade antiviral e virucida em concentrações inferiores a CMNT contra os herpesvírus testados. Assim, o presente trabalho demonstra o potencial de plantas do Cerrado como fonte de compostos com atividade antiviral e virucida. Estudos adicionais são necessários para avaliar os mecanismos de ação e os compostos químicos responsáveis pela atividade observada
Abstract: Herpesviruses are responsible for important diseases in humans and animals. In animals, they are associated with economically important diseases worldwide. In humans, they represent serious threats to public health, and the severity of the illness increases in immunocompromised patients. In addition, there are mutant strains that are resistant to available drugs. Because of the difficulties associated with the prevent ion and treatment of herpesvirus infect ions, the use of plant products as antivirals can be an alternative. The Brazilian Cerrado is a biome located almost entirely in Brazil has over 10,000 species of plants. These plants can potentially be used as a source of pharmacologically active compounds. There for , this study aimed to evaluate the antiviral activity, virucidal activity and the selectivity index (SI) of extracts from Cerrado plants against suid herpesvirus type 1 (SuHV-1) equid type 1 (EHV-1) and herpes simplex virus type 1 (HSV-1). Initially, the lyophilized extracts were tested for cytotoxicity in MDBK and Vero cells to identify t he maximum nontoxic concentration (MNTC). Of the extracts, four showed the same MNTC for both cells, but the extracts were generally more toxic to Vero cells. Then, based on the MNTC, antiviral activity tests were performed against HSV-1 and EHV-1 in Vero cells and SuHV-1 in MDBK cells. The results demonstrated that 50% of the extracts showed activity against at least one of the herpesviruses studied. In particular, the extracts from Banisteriopsis variabil is, Byrsonima intermedia and Xylopia aromatica, were active against all of the herpesviruses, and the extract from Stryphnodendron adstringens was active against HSV-1 and SuHV-1. The extracts that showed antiviral activity were also tested for virucidal activity, and the SI was calculated. An extract was considered active when the viral inhibition index (VII) was greater than or equal to 1.5 or showed a PI% (percent inhibition) greater than or equal to 97%. As for the SI, extracts were considered active when the displayed values greater than or equal to four. Virucidal activity was observed in 75% of the extracts against at least one of the herpesviruses tested. The species that showed the most promising results were: B. variabil is , X. aromatica, S. adstringens and B. intermedia. Was used for additional testing with varying concentrations, and demonstrated antiviral and virucidal activities at concentrations lower than the MNTC against the herpesviruses tested. Therefore, this study demonstrates the potential of Cerrado as a source of compounds with antiviral and virucidal activities. Additional studies are necessary to evaluate the mechanisms of act ion and the chemical compounds responsible for the observed activity
Mestrado
Ciencias Basicas
Mestre em Clinica Medica
31
劉源智 and Yuen-chi Roy Lau. "Response strategies against emergence of antiviral resistance during an influenza pandemic." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B41710666.
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Leung, Yue-hin Ryan, and 梁宇軒. "Effectiveness of antiviral prophylaxis as a containment measure duringan influenza epidemic." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B48424079.
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Influenza epidemics have always been a constant public health threat to human populations. Recent societal developments and demographics changes have put us at increased risk of a widespread and potentially deadly influenza epidemic. Antiviral prophylaxis may provide an important epidemic intervention measure especially against influenza epidemic caused by novel influenza viruses where there will be no effective epidemic-specific vaccines available at the initial phase of the epidemic. Antiviral prophylaxis is listed as a fundamental component of the Hong Kong Preparedness Plan for Influenza Pandemics, however the rationale of such plan is not supported by public presentation of scientific evidence and no details of the actual antiviral prophylaxis plan are provided. With a majority of its stockpile set to expire in the very near future, we would like to know if antiviral prophylaxis is an effective intervention strategy against influenza epidemic and should antiviral stockpiling be continued.
We identified relevant studies and reviewed the effectiveness of antiviral prophylaxis in preventing influenza infections at the individual, household and population level. We found that prophylactic treatment with Oseltamivir or Zanamivir are both effective in preventing influenza infections at the individual and household level. Both antivirals are well tolerated and neither is associated with major adverse events. Antiviral prophylaxis is effective in mitigating the public health impact of an influenza epidemic such as number of clinical influenza infections, hospitalization and deaths. However, antiviral prophylaxis alone may not be sufficient to contain or avert an influenza epidemic or delay the epidemic progress long enough for public health resources such as epidemic-specific vaccines to be acquired. In addition, the emergence of antiviral resistance and various logistics constraints will hamper the effectiveness of antiviral prophylaxis in containing influenza epidemics. We suggest the use of antiviral prophylaxis as the key intervention to mitigate influenza epidemics, however, with special considerations taken into hedging antiviral resistance and fulfilling the logistics requirements in order to make antiviral prophylaxis effective. In addition, we recommend public health authorities to take a multi-factorial approach in tackling highly transmissible influenza epidemics by incorporating other non-pharmaceutical interventions such as quarantine, school closures and boarder restrictions into the their antiviral prophylaxis-based containment plan.published_or_final_version
Public Health
Master
Master of Public Health
33
Mousavi-Jazi, Mehrdad. "Human cytomegalovirus : development of resistance to antiviral drugs and mechanisms of NK-cell evasion /." Stockholm : [Karolinska Univ. Press], 2001. http://diss.kib.ki.se/2001/91-7349-012-1/.
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Ljungdahl, Ståhle Ewa. "In vivo and in vitro models for determination of antiviral activity and resistance /." Stockholm, 1997. http://www.kibic.ki.se/ki/diss/971212ljun.html.
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Janoria, Kumar Gaurav Mitra Ashim K. "Transporter targeted prodrug approach and sustained release formulations for ocular delivery of ganciclovir." Diss., UMK access, 2008.
Find full textAbstract:
Thesis (Ph. D.)--School of Pharmacy and Dept. of Chemistry. University of Missouri--Kansas City, 2008."A dissertation in pharmaceutical sciences and chemistry." Advisor: Ashim K. Mitra. Typescript. Vita. Description based on contents viewed Sept. 12, 2008; title from "catalog record" of the print edition. Includes bibliographical references (leaves 193-204). Online version of the print edition.
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Caras, James William. "Emulation and induction of cytotoxic immunity : immunotoxin therapies for AIDS and novel antiviral vaccines /." Digital version accessible at:, 1999. http://wwwlib.umi.com/cr/utexas/main.
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Gould, Jayne H. M. "The synthesis of novel nucleosides and nucleotides as potential antiviral agents." Thesis, University of Reading, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.339518.
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Coe, Diane Mary. "Synthesis of carbocyclic nucleoside and nucleotide analogues as potential antiviral agents." Thesis, University of Exeter, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294036.
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Perry, Alex. "The synthesis of novel nucleoside phosphate triesters as potential antiviral agents." Thesis, University of Southampton, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243158.
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Ku, Chuen Fai. "Arylnapthalene liguans from justicia plants as potent broad-spectrum antiviral agents." HKBU Institutional Repository, 2020. https://repository.hkbu.edu.hk/etd_oa/779.
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Background: The emergence of viral diseases has been the major threat to public health and social stability. A hundred years ago, 1918 Spanish flu (H1N1) pandemic spread worldwide, and about 3% ~ 5% of the world's population died from the flu-related illnesses. It is known as the deadliest catastrophic pandemics in human history. There have been five Public Health Emergency of International Concern (PHEIC) declarations over the past decade, including the 2014 Ebola outbreak in west Africa, the 2016 Zika outbreak and the ongoing COVID-19 pandemic. There is always a new strain of virus emerging on the horizon. We have urgent need to develop more broad-spectrum antivirals, which work effective against multiple viruses, for thwarting outbreaks in the future. Objective: Based on our previous experience in search of anti-HIV compounds from topical plants, we aimed to discover novel antiviral lead compounds from Justicia plants collected in Hong Kong. Further, structure modification of the natural compounds can lead to optimization of their drug properties for further development as drug candidates. To determine the antiviral targets of the lead compounds will further provide insights to elucidate the mechanism of actions. The present studies are to discover the antiviral lead compounds from Justicia plants, to analyze the structure-activity relationship of the modified structures, to identify the molecular targets of the lead compounds as antiviral agents against the multiple viruses. Methodology: Four common Justicia plants were collected in Hong Kong. The plant extracts and compounds isolated from the plants were explored for their antiviral activities via our established "One-Stone-Two-Birds" antiviral assay. Time-of-addition experiments were performed to determine the target stages of the antiviral compounds on the viral replication. Computational techniques (3D-QSAR and in silico pharmacokinetics evaluation) were employed to elucidate the structure-activity relationship of the compounds and thereby optimize their structures to enhance the antiviral activity. Comprehensive activity-based protein profiling (ABPP) of biotin-linked compounds using SWATH-MS technique was performed to identify the protein target(s) of the lead compounds in an unbiased manner. The role of the molecular target in viral replication was further verified by mRNA knockdown using siRNA. Result: The extracts of Justicia procumbens and Justicia championii showed potent antiviral effects with low cytotoxicity among the collected Justicia plants. By correlating the antiviral activity with their HPLC-UV profiles, arylnaphthalene lignans (ANLs) were determined as the principle active components. Among the isolated compounds from J. procumbens, diphyllin exhibited strong antiviral activities against VSV/HIV, H5N1/HIV and EBOV/HIV pseudoviruses with EC50 values ranging from 30-100nM. In time-of-addition experiments, diphyllin mainly acts on the entry stage of the viral infection. Considering the broad-spectrum antiviral properties and antiviral mechanism together, diphyllin is probably a host-targeting antiviral agent. In a subsequent lead optimization, a reliable and predictive 3D-QSAR was established from 25 synthesized ANLs. Compound 31 was found as the most potent antiviral agent based on the 3D-QSAR model. It showed 70 times more potent antiviral activity than the parent diphyllin, with retained broad-spectrum antiviral properties and improved predicted ADMET properties. In addition, comprehensive ABPP analysis of the biotin-linked diphyllin was employed for the target identification of the ANL compounds. Total 2343 proteins were captured by the ABPP probes. By quantitative analysis, the protein TFAM showed significant affinity to the diphyllin-based ABPP probes. The viral susceptibility of TFAM-deficient cells was shown to be reduced in the subsequent validation. We thus determined TFAM as the potential antiviral drug target of the ANL compounds against a broad spectrum of viruses.
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Ku, Chuen Fai. "Arylnaphthalene lignans from justicia plants as potent broad-spectrum antiviral agents." HKBU Institutional Repository, 2020. https://repository.hkbu.edu.hk/etd_oa/836.
Full textAbstract:
Background: The emergence of viral diseases has been the major threat to public health and social stability. A hundred years ago, 1918 Spanish flu (H1N1) pandemic spread worldwide, and about 3% ~ 5% of the world's population died from the flu-related illnesses. It is known as the deadliest catastrophic pandemics in human history. There have been five Public Health Emergency of International Concern (PHEIC) declarations over the past decade, including the 2014 Ebola outbreak in west Africa, the 2016 Zika outbreak and the ongoing COVID-19 pandemic. There is always a new strain of virus emerging on the horizon. We have urgent need to develop more broad-spectrum antivirals, which work effective against multiple viruses, for thwarting outbreaks in the future. Objective: Based on our previous experience in search of anti-HIV compounds from topical plants, we aimed to discover novel antiviral lead compounds from Justicia plants collected in Hong Kong. Further, structure modification of the natural compounds can lead to optimization of their drug properties for further development as drug candidates. To determine the antiviral targets of the lead compounds will further provide insights to elucidate the mechanism of actions. The present studies are to discover the antiviral lead compounds from Justicia plants, to analyze the structure-activity relationship of the modified structures, to identify the molecular targets of the lead compounds as antiviral agents against the multiple viruses. Methodology: Four common Justicia plants were collected in Hong Kong. The plant extracts and compounds isolated from the plants were explored for their antiviral activities via our established "One-Stone-Two-Birds" antiviral assay. Time-of-addition experiments were performed to determine the target stages of the antiviral compounds on the viral replication. Computational techniques (3D-QSAR and in silico pharmacokinetics evaluation) were employed to elucidate the structure-activity relationship of the compounds and thereby optimize their structures to enhance the antiviral activity. Comprehensive activity-based protein profiling (ABPP) of biotin-linked compounds using SWATH-MS technique was performed to identify the protein target(s) of the lead compounds in an unbiased manner. The role of the molecular target in viral replication was further verified by mRNA knockdown using siRNA. Result: The extracts of Justicia procumbens and Justicia championii showed potent antiviral effects with low cytotoxicity among the collected Justicia plants. By correlating the antiviral activity with their HPLC-UV profiles, arylnaphthalene lignans (ANLs) were determined as the principle active components. Among the isolated compounds from J. procumbens, diphyllin exhibited strong antiviral activities against VSV/HIV, H5N1/HIV and EBOV/HIV pseudoviruses with EC50 values ranging from 30-100nM. In time-of-addition experiments, diphyllin mainly acts on the entry stage of the viral infection. Considering the broad-spectrum antiviral properties and antiviral mechanism together, diphyllin is probably a host-targeting antiviral agent. In a subsequent lead optimization, a reliable and predictive 3D-QSAR was established from 25 synthesized ANLs. Compound 31 was found as the most potent antiviral agent based on the 3D-QSAR model. It showed 70 times more potent antiviral activity than the parent diphyllin, with retained broad-spectrum antiviral properties and improved predicted ADMET properties. In addition, comprehensive ABPP analysis of the biotin-linked diphyllin was employed for the target identification of the ANL compounds. Total 2343 proteins were captured by the ABPP probes. By quantitative analysis, the protein TFAM showed significant affinity to the diphyllin-based ABPP probes. The viral susceptibility of TFAM-deficient cells was shown to be reduced in the subsequent validation. We thus determined TFAM as the potential antiviral drug target of the ANL compounds against a broad spectrum of viruses.
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Sellitto, Grazia. "Design and synthesis of “small molecules” as antiviral and radiotracer agents." Doctoral thesis, Universita degli studi di Salerno, 2011. http://hdl.handle.net/10556/142.
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2009 - 2010The present Ph.D. project was divided into different work parts, in a way that helps to understand and define the goals of this project. In particular: I) Design, synthesis and evaluation of antiviral activity of Arbidol analogs. II) Evaluation of mechanism of Arbidol anti-influenza action. III) Synthesis and characterization of a P.E.T. radiotracer for tumor hypoxia: 1- (5- [18F] Fluoro-5-deoxy-α-D-arabinofuranosyl) -2-nitroimidazole or 18F-FAZA. The initial research activity concerned the design and synthesis of indole derivatives using as a lead compound Arbidol (ARB), a compound that exerts immunomodulatory, antioxidant, antiviral and antimetastatic effects1. ARB is a Russian-made potent broad-spectrum antiviral with demonstrated activity against a number of DNA and RNA viruses, enveloped and non-enveloped viruses, and pH-dependent and pH-independent viruses. It exhibits antiviral activity against a number of viruses including influenza A (H1N1, H2N2 and H3N2), B and C viruses, respiratory syncytial virus (RSV), adenovirus type 7, coxsackie B3 virus, parainfluenza type 5 and rhinovirus type 14, avian coronavirus, infectious bronchitis virus and Marek disease virus, hepatitis B virus and hepatitis C virus. The wide spectrum of ARB’s activity suggests that ARB targets common critical step(s) in virus – cell interaction. Several studies have shown that the affinity of ARB for lipid membranes could account for its antiviral actions, together with a differential level of interaction with key motifs in glycoproteins of different viruses. Its antiviral activity toward viruses is due probably to a direct effect of ARB on virus-cell membrane interactions where ARB intercalates into membranes and induces membrane alterations. This leads to excessive stabilization of cell membranes, which become resistant to virus fusion and in some cases (HCV) to virus replication2-4. The known biological properties of Arbidol led us to focus on its derivatives as potential antiviral agents. In order to maintain antiviral activity we preserved the groups responsible of Arbidol interaction with membranes (indole ring, S-phenyl group, ester group and amino group) eliminating those that were not considered pharmacophores (hydroxy and bromo groups at the 5- and 6-positions of the indole ring). Moreover we introduced different substituents at the 2- and 5-position of the indole ring to investigate the influence of these variations on antiviral activity. The synthesis of Arbidol derivatives has been established through the validation of two synthetic schemes. Then, to evaluate anti-HCV and anti-HSV activity of synthesized compounds, biological assays were made. ARB derivatives showed antiviral activity comparable and, in some cases, even better than those of lead Arbidol, on both systems. In particular, it was shown that synthesized compounds are fusion inhibitors on both viruses and also non-selective inhibitors of HCV replication. The second part of the present research project concerned the study of mechanism of Arbidol anti-influenza action. There are experimental evidences that ARB does not affect viral neuraminidase (NA, a surface protein of influenza virus) activity. It affects early post-adsorption stages of virus replication with possible involvement of the second surface viral protein, the haemagglutinin (HA). Arbidol could act increasing influenza virus HA stability and preventing low pH induced HA transition to its fusogenic state, thus blocking infection at the viral fusion stage5. To support this hypothesis, the interaction of Arbidol with the N-terminal hydrophobic fusion domain of haemagglutinin (HA) was evaluated. Therefore, the peptide host-guest (P20H6) was synthesized using techniques of Solid Phase Peptide Synthesis (SPPS) and Circular dichroism studies were made6.From these studies we demonstrated that Arbidol interacts with the haemagglutinin fusion domain at pH 5 and 7, through changes in the secondary structure of peptide. At the end of present Ph.D. project, I spent six months at the University of Aberdeen where I worked to the synthesis of a PET (Positron Emission Tomography) radiotracer for tumour hypoxia: the [18F]1-α-D-(5-Fluoro-5-deoxyarabinofuranosyl)-2-nitroimidazole, known as 18F-FAZA. 18F-FAZA is currently the gold standard for PET Imaging of diseases characterized by hypoxia (solid tumours, ischemia, stroke)7, but it is not routinely used and synthesized in Scotland. The work done is an important starting point for the introduction of 18F-FAZA in Scotland with the aim of using it in clinical imaging and research. In particular, following a detailed bibliography research on this compound and its synthesis, that is not fully reported, and a subsequent optimization of the synthetic scheme used, the 18F-FAZA precursor was obtained: 1-α-D-[5’-O-Toluenesulfonyl-2’,3’-Di-Oacetylarabinofuranosyl]-2-nitroimidazole (DAcTs-AZA). [edited by author]
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Defant, Andrea. "Design, Chemical Synthesis and Biological Evaluation of Potential New Antiviral Agents." Doctoral thesis, Università degli studi di Trento, 2012. https://hdl.handle.net/11572/368092.
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Acquired Immunodeficiency Syndrome (AIDS) is a disease caused by the Human Immunodeficiency Virus (HIV). Since its discovery in 1981, more than 25 million people died due to this disease. To date, an effective HIV-1 vaccine usable in prophylaxis or in the therapy of humans has not yet been identified. The failures and limited success of HIV vaccines have reinforced the role of chemotherapy and therefore research on the development of effective drugs. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) were the early agents introduced in the therapy and currently they are the most used, based on their concurrent high activity against the virus and low toxicity against human cells. In addition, the rapid development of virus resistance against these types of drugs, needs to find new molecules able to overcome this drawback.
My thesis work started from the design of a small library of new molecules, with hybrid structures based on a template deriving from the natural product (+)-calanolide A and the synthetic molecule α-APA, both showing a potent and selective activity against reverse transcriptase. Docking calculation has allowed to select molecules having the best values of interaction energy with the viral enzyme. Chemical synthesis was carried out together with structural characterization by extensive spectroscopic analysis including NMR technique and mass spectrometry.
In particular, the synthesis of the amide group present in the structure of some amino-pyrone compounds using the standard method, resulted in the expected N-acylation, but with a C-acyl byproduct. This result has suggested to look further into the study of N,C-acylation selectivity for the ambidentate amino-pyrone moiety, whose reactivity is poorly known. Regioselectivity was investigated under different conditions (organic bases, solvent, acylating agent), also for an enamino-ester taken as a model compound. Experimental procedures were optimized in order to synthesize selectively pure N- and C-acylated compounds.
A preliminary enzymatic assay indicated a good activity in the early prepared compounds of the series, promising for the following in vitro tests on HIV infected cells of each molecule in the whole series. In addition, these compounds were tested against other common viruses for human infective pathologies. With the aim of identifying molecules with potential therapeutic applications, the antiviral activity must be related to cytostatic effect, in order to select the ones with a favored selectivity index. Unfortunately, the molecules showed paragonable values in antiviral and cytostatic effects, the latter one not easily predictable neither by the chemical structure, nor by a computational approach.
If the drug design by molecular docking has failed in selecting a new scaffold for NNRTIs, the study has driven the interest towards new potential antitumoral molecules showing activity at sub-micromolar concentration against leukemic cell lines.
Due to the structural similarity with recently studied antibacterial natural pyrones, the synthetic molecules showing the lowest values of cytotoxicity were investigated in the inhibition of bacterial strains. Some tested compounds have shown a good activity and selectivity against Gram(+) bacteria.
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Defant, Andrea. "Design, Chemical Synthesis and Biological Evaluation of Potential New Antiviral Agents." Doctoral thesis, University of Trento, 2012. http://eprints-phd.biblio.unitn.it/859/1/Andrea_Defant_thesis.pdf.
Full textAbstract:
Acquired Immunodeficiency Syndrome (AIDS) is a disease caused by the Human Immunodeficiency Virus (HIV). Since its discovery in 1981, more than 25 million people died due to this disease. To date, an effective HIV-1 vaccine usable in prophylaxis or in the therapy of humans has not yet been identified. The failures and limited success of HIV vaccines have reinforced the role of chemotherapy and therefore research on the development of effective drugs. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) were the early agents introduced in the therapy and currently they are the most used, based on their concurrent high activity against the virus and low toxicity against human cells. In addition, the rapid development of virus resistance against these types of drugs, needs to find new molecules able to overcome this drawback.
My thesis work started from the design of a small library of new molecules, with hybrid structures based on a template deriving from the natural product (+)-calanolide A and the synthetic molecule α-APA, both showing a potent and selective activity against reverse transcriptase. Docking calculation has allowed to select molecules having the best values of interaction energy with the viral enzyme. Chemical synthesis was carried out together with structural characterization by extensive spectroscopic analysis including NMR technique and mass spectrometry.
In particular, the synthesis of the amide group present in the structure of some amino-pyrone compounds using the standard method, resulted in the expected N-acylation, but with a C-acyl byproduct. This result has suggested to look further into the study of N,C-acylation selectivity for the ambidentate amino-pyrone moiety, whose reactivity is poorly known. Regioselectivity was investigated under different conditions (organic bases, solvent, acylating agent), also for an enamino-ester taken as a model compound. Experimental procedures were optimized in order to synthesize selectively pure N- and C-acylated compounds.
A preliminary enzymatic assay indicated a good activity in the early prepared compounds of the series, promising for the following in vitro tests on HIV infected cells of each molecule in the whole series. In addition, these compounds were tested against other common viruses for human infective pathologies. With the aim of identifying molecules with potential therapeutic applications, the antiviral activity must be related to cytostatic effect, in order to select the ones with a favored selectivity index. Unfortunately, the molecules showed paragonable values in antiviral and cytostatic effects, the latter one not easily predictable neither by the chemical structure, nor by a computational approach.
If the drug design by molecular docking has failed in selecting a new scaffold for NNRTIs, the study has driven the interest towards new potential antitumoral molecules showing activity at sub-micromolar concentration against leukemic cell lines.
Due to the structural similarity with recently studied antibacterial natural pyrones, the synthetic molecules showing the lowest values of cytotoxicity were investigated in the inhibition of bacterial strains. Some tested compounds have shown a good activity and selectivity against Gram(+) bacteria.
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CIANCIMINO, Cristina. "Synthesis of Azole-Heterocycles as Potential Antitumor and/or Antiviral Agents." Doctoral thesis, Università degli Studi di Palermo, 2014. http://hdl.handle.net/10447/90986.
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Rodrigues, Ana Mara Lopes. "Interferon, virus vaccines and antiviral drugs." Thesis, University of St Andrews, 2008. http://hdl.handle.net/10023/428.
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The emergence of viruses with zoonotic potential, i.e. with the potential ability to cross species barriers to infect unnatural hosts, poses a huge threat to humans. It is therefore essential to develop new methodologies to rapidly and efficiently generate attenuated virus vaccine candidates to attempt to control the threat. Viruses need to be able to at least partially inhibit the host’s innate defence mechanism, known as the interferon (IFN) system, to replicate efficiently in vivo and establish a productive infection. It has been previously reported that viruses that have lost their ability to circumvent the host’s IFN response, or IFN-sensitive viruses, are promising candidates for live attenuated virus vaccines. Here we report on the development of a cell-based method to attempt to rapidly select IFN-sensitive viruses that can not block IFN signalling, from wild-type virus populations. Lentivirus vectors containing selection markers (HSV-tk – Herpes Simplex virus thymidine kinase gene and pac – puromycin resistance gene) under the control of a tight IFN-inducible promoter (the murine Mx1 promoter) were generated and used to specifically engineer HEp2 cell lines, termed Mx GIPSE and Mx TIPSE, for this purpose. The developed methodology relies on the engineered cell lines and a selection procedure using exogenous IFN-α and puromycin: if a cell is infected with IFN-resistant virus, it will die in the presence of IFN-α and puromycin because IFN signalling will be blocked, thereby blocking the activation of the Mx1 promoter and consequent expression of pac; if a cell is infected with an IFN-sensitive virus, it will survive in the presence of IFN-α and puromycin because the Mx1 promoter will become activated through the IFN signalling pathway, leading to the expression of pac. IFN-sensitive viruses can then be rescued from the surviving cells, and amplified using IFN-permissive cell lines expressing viral IFN antagonist proteins (proteins that block the host’s IFN response). When tested on PIV5 strains CPI- (an IFN-sensitive virus) and CPI+ (an IFN-resistant virus), the developed method allowed the survival and amplification of cells infected with CPI-, whilst cell death was observed for cells infected with CPI+. Whilst the developed methodology seems promising, further developments of the system are required. The possibilities of using the developed methodology in combination with other techniques, such as FACS sorting and immune selection, to rapidly select IFN-sensitive mutant viruses from wild-type and mutagenised virus populations are discussed. The potential to use Mx TIPSE cells to select IFN-resistant revertant viruses from IFN-sensitive virus populations is also discussed. In addition, a high throughput screening assay has been developed using the engineered Mx GIPSE and Mx TIPSE cell lines to search for compounds that block IFN signalling or that block the action of viral IFN antagonist proteins. Compounds that block IFN signalling would potentially be useful as anti-inflammatory drugs whilst compounds that block the action of viral IFN antagonist proteins would be valuable as antiviral drugs.
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Carlsson, Tony. "Hepatitis C virus kinetics during antiviral treatment /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-588-3/.
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Bastos, Juliana Cristina Santiago 1985. "Atividade antiviral de organismos marinhos frente ao vírus da diarreia viral bovina, modelo para o vírus da hepatite C." [s.n.], 2013. http://repositorio.unicamp.br/jspui/handle/REPOSIP/316637.
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Orientadores: Clarice Weis Arns, Luciana Konecny KohnDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia
Made available in DSpace on 2018-08-22T21:48:22Z (GMT). No. of bitstreams: 1 Bastos_JulianaCristinaSantiago_M.pdf: 1673040 bytes, checksum: 1234828d961406573d21b2476f1f1800 (MD5) Previous issue date: 2013
Resumo: O vírus da Hepatite C (família Flaviviridae, gênero Hepacivirus) é causador de infecções crônicas em humanos, que podem evoluir para quadros de cirrose hepática e carcinoma hepatocelular. Até o momento, não há vacina disponível contra essa infecção e o tratamento disponível é caro, tem eficácia limitada e gera uma vasta gama de efeitos secundários, o que dificulta a continuidade do tratamento. Como esse vírus não replica eficientemente em cultura de células e em animais, o vírus da diarréia viral bovina é utilizado como modelo substituto para ensaios de avaliação de atividade antiviral e em ensaios de mecanismo de ação. A partir de invertebrados e micro-organismos marinhos, foram preparados extratos e frações, e algumas substâncias foram isoladas para a avaliação da sua possível atividade antiviral. Dos 422 testados, 5% foram considerados promissores e, destes, 20% mostraram-se ativos apresentando uma proteção de mais de 97% às células frente ao vírus. Os melhores resultados foram obtidos dos extratos produzidos a partir das amostras de esponjas Hyrtios sp. (BA07ES-56: PI=99%, IS=25), Aaptos sp. (BA07ES-59: PI=99%, IS=8,25) e de bactérias Bacillus sp. (555: PI=98%, IS>18; 584: PI=98%, IS=27) isoladas da esponja Petromica citrina. Os extratos e compostos promissores foram capazes de atuar em diversas etapas do ciclo replicativo viral (adsorção, penetração, etapas intracelulares do ciclo replicativo e também inativação da partícula viral), levando à sua interrupção quase completa nas condições analisadas. Desse modo, diversas substâncias presentes nesses organismos estudados são ativas e podem levar ao desenvolvimento de fármacos que garantam uma terapia alternativa para o tratamento da hepatite C
Abstract: The Hepatitis C virus (family Flaviviridae, genus Hepacivirus) causes chronic infections in humans, which can develop to liver cirrhosis and hepatocellular carcinoma. This represents a major public health problem worldwide. To this moment, there is no vaccine available against this infection and the treatment available is expensive, has limited efficacy and generates a wide range of side effects, making it difficult to continue the treatment. All this reflects the need to seek new agents with antiviral action against this virus. As this virus does not replicate efficiently in cell culture and in animals, bovine viral diarrhea virus is used as a surrogate model for screening assays of antiviral activity, and mechanism of action assays. From marine invertebrates and micro-organisms isolated from them, extracts and fractions were prepared, and substances were isolated for assessment of their possible antiviral activity. Of the 422 tested, 5% were considered promising, and of these, 20% were active presenting a protection percentage of more than 97%. The best results were obtained from the extracts produced from the samples of sponge Hyrtios sp. (BA07ES-56: IP=99%, SI=25), Aaptos sp. (BA07ES-59: IP=99%, SI=8,25) and bacteria Bacillus sp. (555: IP=98%, SI>18; 584: IP=98%, SI=27) isolated from the sponge Petromica citrina. The promising extracts and compounds acted in several stages of viral replicative cycle (adsorption, penetration, intracellular steps of the replicative cycle and also inactivation of the viral particle). Thus, various substances are active and may lead to the development of drugs which ensure an alternative therapy for the treatment of hepatitis C
Mestrado
Microbiologia
Mestra em Genética e Biologia Molecular
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Meister, Gabriel T. "Antiviral mechanism(s) of the experimental immunosuppressive agent leflunomide against human cytomegalovirus and polyomavirus." Connect to this title online, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1111428519.
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Thesis (Ph. D.)--Ohio State University, 2005.Title from first page of PDF file. Document formatted into pages; contains xiii, 127 p.; also includes graphics (some col.) Includes bibliographical references (p. 113-127). Available online via OhioLINK's ETD Center
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Petit, Roig Elena. "Bioconjugació de poliols i tiols amb agents antivírics." Doctoral thesis, Universitat de Barcelona, 2019. http://hdl.handle.net/10803/667891.
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El VIH-1 segueix essent un dels problemes més greus de la sanitat pública mundial, especialment als països del tercer món. La fase més avançada de la infecció pel VIH és la SIDA (síndrome d’immunodeficiència adquirida).
La present Tesi Doctoral descriu els nostres esforços en la síntesi d’una nova generació de microbicides (4a generació), uns conjugats de fàrmacs antivirals a estructures polimèriques o suports per aconseguir un agent tòpic amb una absorció controlada.
Així, després d’una introducció sobre la SIDA i els microbicides, el Capítol 1 tracta de l’obtenció de 14 anàlegs del BMS806, els quals, gràcies a la col·laboració amb el Laboratori d’Immunobiologia Molecular, es va poder assajar biològicament com inhibidors d’entrada, concloent que els millors candidats eren els productes obtinguts substituïts a la posició C7 de l’indol o indole.
El Capítol 2 inclou l’obtenció de més derivats dels BMS806, assajant la cicloaddició [3+2] catalitzada per salts de Cu(I) dels azidoderivats del Capítol 1. També s’han sintetitzat diferents lligands capaços d’estabilitzar els ions de Cu(I) enfront de l’oxidació i de solubilitzar els complexos de Cu(I) que es formen, per ajudar a disminuir la citotoxicitat d’aquesta reacció. A més a més, es va intentar preparar un lligand nou, tot i que sense èxit. S’han optimitzat les condicions per dur a terme la reacció de cicloaddició [3+2] per a substrats tant polars com la βCD en medis aquosos, aconseguint reduir significativament la quantitat de Cu(I) amb l’ajuda d’un lligand.
Dins del tema de reaccions de tipus click, en el Capítol 3 es presenta el desenvolupament d’un mètode bioortogonal basat en addicions conjugades simples de tiols a triples enllaços terminals activats en condicions fisiològiques i sense additius.
La conjugació de fàrmacs amb anticossos, biomolècules i macromolècules està esdevenint, cada vegada més, una estratègia d’especial interès en l’àmbit biomèdic. A més, també és sabut que permet desenvolupar vies menys tòxiques d’administració de medicaments. Amb l’objectiu d’aconseguir un gel microbicida, en el Capítol 4 s’exposa la síntesi de diferents conjugats entre la βCD i els millors candidats anàlegs del BMS806 mitjançant la reacció de cicloaddició [3+2], que s’han pogut assajar biològicament. Satisfactòriament, es va comprovar que els productes substituïts a la posició 7 de l’indol inhibeixen clarament la infecció per VIH-1 (tant de la soca X4 com la R5).
En aquest mateix capítol, també es recullen les millors condicions per a la síntesi del HPG i diferents anàlegs, un polímer amb una excel·lent biocompatibilitat, d’estructura compacta, globular, versàtil pel que fa a la seva funcionalització i, pensem, bon candidat com a suport del fàrmac per aconseguir el microbicida desitjat. També s’ha conjugat el HPG amb derivats del BMS mitjançant les dues vies estudiades durant la Tesi, la cicloaddició [3+2] i l’addició conjugada de tiols a propinamides.
Finalment, en el Capítol 5 de la present Tesi es mostren tots els resultats recollits, en el Laboratori d’Immunobiologia Molecular de l’Hospital General Universitario Gregorio Marañon de Madrid, pel que fa a la citotoxicitat de tots els productes analitzats i a la inhibició del VIH. Hi ha percentatges d’infecció de les cèlul·les, després de l’exposició al virus, que són molt prometedors.HIV-1 is still one of the most serious problems of global public health, especially in third world countries. The most advanced stage of HIV infection is AIDS (acquired immunodeficiency syndrome). The present Doctoral Thesis describes our efforts in the synthesis of a new generation of microbicides (4th generation), which are conjugates of antiviral drugs to polymeric structures or scaffolds to achieve a topical agent with controlled absorption. Thus, after an introduction on AIDS and microbicides, Chapter 1 deals with the preparation of 14 analogues of BMS806, which could be biologically tested as entry inhibitors, concluding that the best candidates were the products substituted on position 7 of indole. Chapter 2 includes the preparation of more derivatives of BMS806, testing the Cu(I)-catalyzed [3+2] cycloaddition of the azides shown in Chapter 1. Also, several ligands have been synthesized to reduce the cytotoxicity of this reaction. The conditions for carrying out the [3+2] cycloaddition reaction with polar substrates such as βCD in aqueous media have been optimized. Within the click reactions, Chapter 3 presents the development of a bioortogonal method based on the simple conjugate additions of thiols to activated terminal triple bonds under physiological conditions, without additives. In order to achieve a microbicide gel, Chapter 4 presents the synthesis of different conjugates from βCD and the best analogous candidates of BMS806 by [3+2] cycloaddition, which could be tested biologically. Also Chapter 4, we summarize the best conditions for the synthesis of HPG and analogues, a good candidate as a drug support to achieve the desired microbicide. HPG was also conjugated with BMS derivatives through the two reactions studied during this Thesis, the [3+2] cycloaddition and the conjugated addition of thiols to propynamides. Finally, in Chapter 5 all the results obtained in the Laboratory of Molecular Immunobiology at the Gregorio Marañón General University Hospital in Madrid were collected. Cytotoxicity and inhibition of HIV of all samples were analyzed. Some products afford percentages of infection of the cells, after exposure to the virus, which are very promising.