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Leonardo Dos Santos Corrêa Amorim Avaliação De UNIVERSIDADE FEDERAL FLUMINENSE INSTITUTO DE BIOLOGIA PROGRAMA DE PÓS-GRADUAÇÃO EM CIÊNCIAS E BIOTECNOLOGIA LEONARDO DOS SANTOS CORRÊA AMORIM AVALIAÇÃO DE SUBSTÂNCIAS NATURAIS EXTRAÍDAS DAS ALGAS MARINHAS Dictyota friabilis E Osmundaria obtusiloba E SUBSTÂNCIAS SINTÉTICAS DERIVADOS DE NAFTOQUINONAS E QUINOLINAS FRENTE AOS VÍRUS DE IMPORTÂNCIA CLÍNICA (HIV-1, ZIKV, HSV-1 e MAYV). Tese de Doutorado submetida à Universidade Federal Fluminense como requisito parcial visando à obtenção do grau de Doutor em Ciências e Biotecnologia. Orientador(es): Izabel Christina Nunes de Palmer Paixão Claudio Cesar Cirne dos Santos NITERÓI 2020 I LEONARDO DOS SANTOS CORRÊA AMORIM AVALIAÇÃO DE SUBSTÂNCIAS NATURAIS EXTRAÍDAS DAS ALGAS MARINHAS Dictyota friabilis E Osmundaria obtusiloba E SUBSTÂNCIAS SINTÉTICAS DERIVADOS DE NAFTOQUINONAS E QUINOLINAS FRENTE AOS VÍRUS DE IMPORTÂNCIA CLÍNICA (HIV-1, ZIKV, HSV-1 e MAYV). Trabalho desenvolvido no Laboratório de Virologia Molecular do Departamento de Biologia Celular e Molecular do Instituto de Biologia, Programa de Pós- Graduação em Ciências e Biotecnologia, Universidade Federal Fluminense. Apoio Financeiro: CAPES, CNPq, FAPERJ, UFF-FOPESQ. Tese de Doutorado submetida à Universidade Federal Fluminense como requisito parcial visando à obtenção do grau de Doutor em Ciências e Biotecnologia. Orientador(es): Izabel Christina Nunes de Palmer Paixão Claudio Cesar Cirne dos Santos II Ficha catalográfica automática - SDC/BCV Gerada com informações fornecidas pelo autor C824a Corrêa amorim, Leonardo dos Santos AVALIAÇÃO DE SUBSTÂNCIAS NATURAIS EXTRAÍDAS DAS ALGAS MARINHAS Dictyota friabilis E Osmundaria obtusiloba E SUBSTÂNCIAS SINTÉTICAS DERIVADOS DE NAFTOQUINONAS E QUINOLINAS FRENTE AOS VÍRUS DE IMPORTÂNCIA CLÍNICA (HIV-1, ZIKV, HSV-1 e MAYV). / Leonardo dos Santos Corrêa amorim ; Izabel Christina Nunes de Palmer Paixão, orientadora ; Cláudio César Cirne dos Santos, coorientadora. Niterói, 2020. 157 f. : il. Tese (doutorado)-Universidade Federal Fluminense, Niterói, 2020. DOI: http://dx.doi.org/10.22409/PPBI.2020.d.11344133789 1. Antivirais. 2. Vírus de Importância Clínica. 3. Substâncias Naturais. 4. Substâncias Sintéticas. 5. Produção intelectual. I. Paixão, Izabel Christina Nunes de Palmer, orientadora. II. Cirne dos Santos, Cláudio César, coorientadora. III. Universidade Federal Fluminense. Instituto de Biologia. IV. Título. CDD - Bibliotecário responsável: Sandra Lopes Coelho - CRB7/3389 LEONARDO DOS SANTOS CORRÊA AMORIM AVALIAÇÃO DE SUBSTÂNCIAS NATURAIS EXTRAÍDAS DAS ALGAS MARINHAS Dictyota friabilis E Osmundaria obtusiloba E SUBSTÂNCIAS SINTÉTICAS DERIVADOS DE NAFTOQUINONAS E QUINOLINAS FRENTE AOS VÍRUS DE IMPORTÂNCIA CLÍNICA (HIV-1, ZIKV, HSV-1 e MAYV). Tese de Doutorado submetida à Universidade Federal Fluminense como requisito parcial visando à obtenção do grau de Doutor em Ciências e Biotecnologia. Banca Examinadora _______________________________________________________________ Viveca Antonia Giongo Galvão da Silva – Universidade Estácio de Sá _______________________________________________________________ Juliana Eymara Fernandes Barbosa Paula – Hospital Universitário Gafree Guinle – UNIRIO. _______________________________________________________________ Ana Maria Viana Pinto – Instituto Biomédico – UFF _______________________________________________________________ Patrícia Burth – Instituto de Biologia – UFF. _______________________________________________________________ Helena Carla Castro – Instituto de Biologia – UFF. _______________________________________________________________ Juliana Silva Novais – Instituto de Biologia – UFF. _______________________________________________________________ Rosa Teixeira de Pinho – Instituto Oswaldo Cruz – Fiocruz. _______________________________________________________________ Izabel Christina Nunes de Palmer Paixão – Instituto de Biologia – UFF. _______________________________________________________________ Claudio Cesar Cirne dos Santos – Instituto de Biologia – UFF. III Dedico este meu trabalho aos meus avós, pais e irmão que sempre fizeram de tudo para que eu realizasse o meu sonho, aos meus orientadores a todos os amigos, por me ajudarem a torná-lo possível. IV AGRADECIMENTOS Acho justo começar este agradecimento citando um trecho de uma música da qual raramente ouço, porém, nunca se fez tão literal em minha vida. “Você não sabe o quanto eu caminhei, para chegar até aqui...”, nenhuma frase poderia exprimir melhor minha trajetória. Agradeço à Deus, e a toda e qualquer força astral superior que possa ter me auxiliado de alguma forma a atingir meus objetivos. A esta universidade, sеu corpo docente, direção е administração que oportunizaram а janela que hoje vislumbro um horizonte superior, eivado pela acendrada confiança no mérito е ética aqui presentes. Agradeço а todos os professores por me proporcionar о conhecimento não apenas racional, mas а manifestação do caráter е afetividade da educação no processo de formação profissional, por tanto que se dedicaram а mim, não somente por terem me ensinado, mas por terem me feito aprender. А palavra mestre, nunca fará justiça aos professores dedicados aos quais sem nominar terão os meus eternos agradecimentos. A minha orientadora, pelo emprenho dedicado à elaboração deste trabalho. Aos momentos dispensados a mim, seja para uma conversa científica ou simplesmente pelos momentos de amizades, ambos sempre muito gratificantes e construtivos. Agradeço aos meus pais e irmão por todo amor, incentivo e apoio incondicional! Se me tornei o homem que sou hoje, com certeza foi pelo esforço dedicado a mim desde sempre. Por não medirem esforços e sempre me incentivarem a continuar lutando por meus sonhos e objetivos, mesmo e principalmente quando eu tinha vontade de desistir. Agradeço também aos meus familiares que sempre confiaram em minha capacidade e sempre proferiram palavras de incentivo e orgulho. Aos meus amigos, serei eternamente grato! Pois sempre estiveram ao meu lado e me ajudaram a superar as adversidades mesmo não havendo obrigação. Fizeram-se presentes em momentos únicos da minha trajetória e V mostraram, que a amigos de verdade são raros, mas quando encontrado, são extremamente valiosos! Agradeço também aos meus amigos de trabalho, que se fizeram importantes em várias etapas da minha vida acadêmica, me auxiliando em análises, experimentos e na manutenção da sanidade mental que muitas vezes perdemos entre uma tarefa e outra. Para terminar, parafraseio um dos maiores educadores e pensadores brasileiros: “...para mim, é impossível existir sem sonho. A vida na sua totalidade me ensinou como grande lição que é impossível assumí-la sem risco.” (Paulo Freire). O presente trabalho foi realizado com apoio da Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Código de Financiamento 001. VI SUMÁRIO AGRADECIMENTOS ......................................................................................... V SUMÁRIO ........................................................................................................ VII LISTA DE ABREVIATURAS ............................................................................. IX LISTA DE ILUSTRAÇÕES .............................................................................. XII LISTA DE TABELA ........................................................................................ XIII RESUMO........................................................................................................ XIV ABSTRACT ..................................................................................................... XV 1. ANTIVIRAIS ................................................................................................ 1 1.1. HISTÓRICO .......................................................................................... 1 1.1.1. ANÁLOGOS DE NUCLEOSÍDEO .................................................. 2 1.1.2. ANÁLOGOS DE PIROFOSFATO .................................................. 5 1.1.3. INIBIDORES NUCLEOSÍDEOS DA TRANSCRIPTASE RESERVA 6 1.1.4. INIBIDORES NÃO NUCLEOSÍDEOS DA TRANSCRIPTASE REVERSA ................................................................................................... 7 1.1.5. INIBIDORES DE PROTEASE ........................................................ 7 1.1.6. INIBIDORES DE INTEGRASE ....................................................... 9 1.1.7. INIBIDORES DE ENTRADA ........................................................ 10 1.1.8. INIBIDORES ANÁLOGOS DA GUANOSINA ACÍCLICOS ......... 13 1.1.9. INIBIDORES ANÁLOGOS FOSFANATOS DE NUCLEOSÍDEO ACÍCLICO ................................................................................................. 15 1.1.10. INIBIDORES DO NS5A/NS5B DO HCV ................................... 18 1.1.11. INIBIDORES DOS VÍRUS INFLUENZA .................................... 20 1.1.12. INIBIDORES A BASE DE INTERFERONS, IMUNOESTIMULADORES, OLIGONUCLEOTÍDEOS E ANTIMITÓTICOS. 23 1.2. IMPORTÂNCIA BIOTECNOLÓGICA ................................................. 25 1.3. A IMPORTÂNCIA DA ESTRUTURA E REPLICAÇÃO VIRAL PARA OS ANTIVIRAIS............................................................................................ 28 2. DISCUSSÃO ............................................................................................. 36 ATIVIDADE ANTIVIRAL DAS ALGAS MARINHAS Dictyota friabilis E Osmundaria obtusiloba. ............................................................................. 36 Diterpene From Marine Brown Alga Dictyota friabilis As A Potential Microbicide Against
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