| Author | Souza, Thiago Moreno L. | |
| Author | Rodrigues, Diego Q. | |
| Author | Ferreira, Vitor F. | |
| Author | Marques, Isakelly Pereira | |
| Author | Santos, Fernanda da Costa | |
| Author | Cunha, Anna Claudia | |
| Author | Souza, Maria Cecília Bastos Vieira de | |
| Author | Frugulhetti, Izabel Christina de Palmer Paixão | |
| Author | Bou-Habib, Dumith Chequer | |
| Author | Fontes, Carlos Frederico Leite | |
| Access date | 2018-08-16T18:00:46Z | |
| Available date | 2018-08-16T18:00:46Z | |
| Document date | 2009 | |
| Citation | SOUZA, Thiago Moreno L. et al. Characterization of HIV-1 Enzyme Reverse Transcriptase Inhibition by the Compound 6-Chloro-1,4-Dihydro-4-Oxo-1-(-D-Ribofuranosyl) Quinoline-3-Carboxylic Acid Through Kinetic and In Silico Studies. Current HIV Research. v.7, p.327-335, 2009. | pt_BR |
| ISSN | 1570-162X | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/28197 | |
| Language | eng | pt_BR |
| Publisher | Bentham Science Publishers | pt_BR |
| Rights | restricted access | |
| Subject in Portuguese | HIV-1 | pt_BR |
| Subject in Portuguese | Ácido cloroxoquinolínico | pt_BR |
| Subject in Portuguese | AIDS | pt_BR |
| Subject in Portuguese | Transcriptase reversa | pt_BR |
| Title | Characterization of HIV-1 Enzyme Reverse Transcriptase Inhibition by the Compound 6-Chloro-1,4-Dihydro-4-Oxo-1-(-D-Ribofuranosyl) Quinoline-3-Carboxylic Acid Through Kinetic and In Silico Studies | pt_BR |
| Type | Article | |
| Abstract | We recently described that the chloroxoquinolinic ribonucleoside 6-chloro-1,4-dihydro-4-oxo-1-(-Dribofuranosyl)
quinoline-3-carboxylic acid (compound A) inhibits the human immunodeficiency virus type 1 (HIV-1) enzyme
reverse transcriptase (RT), and its replication in primary cells. Based on these findings, we performed kinetic studies
to investigate the mode of inhibition of compound A and its aglycan analog (compound B). We found that both molecules
inhibited RT activity independently of the template/primer used. Nevertheless, compound A was 10-fold more potent
than compound B. Compound A inhibited the RNA-dependent DNA polymerase (RDDP) activity of RT with an uncompetitive
and a noncompetitive mode of action with respect to dTTP incorporation and to template/primer (TP) uptake,
respectively. The kinetic pattern of the inhibition displayed by compound A was probably due to its greater affinity for the
ternary complex (RT-TP-dNTP) than the enzyme alone or the binary complex (RT-TP). Besides, by means of molecular
modeling, we show that compound A bound on the NNRTI binding pocket of RT. However, our molecule targets such a
site by making novel interactions with the enzyme RT, when compared to NNRTIs. These include a hydrogen bridge between
the 2’-OH of our compound and the Tyr675 of the enzyme RT’s chain B. Therefore, compound A is able to synergize
with both a NRTI (AZT-TP) and a NNRTI (efavirenz). Taken together, our results suggest that compound A displays
a novel mechanism of action, which may be different from classical NRTIs and NNRTIs. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Vírus Respiratórios e do Sarampo. Rio de Janeiro, RJ. Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ. Brasil. | pt_BR |
| Affilliation | Universidade Federal Fluminense. Instituto Química. Departamento de Química Orgânica. Laboratório de Nucleosídeos. Niterói, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal Fluminense. Instituto Química. Departamento de Química Orgânica. Laboratório de Nucleosídeos. Niterói, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal Fluminense. Instituto Química. Departamento de Química Orgânica. Laboratório de Nucleosídeos. Niterói, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal Fluminense. Instituto Química. Departamento de Química Orgânica. Laboratório de Nucleosídeos. Niterói, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal Fluminense. Instituto Química. Departamento de Química Orgânica. Laboratório de Nucleosídeos. Niterói, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal Fluminense. Instituto de Biologia. Departamento de Biologia Celular e Molecular. Laboratório de Virologia Molecular. Niterói, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ. Brasil. | pt_BR |
| Affilliation | Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Médica Leopoldo de Meis. Laboratório de Estrutura e Regulação de Proteínas. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Subject | HIV-1 | pt_BR |
| Subject | AIDS | pt_BR |
| Subject | Reverse transcriptase | pt_BR |
| Subject | Chloroxoquinolinic acid | pt_BR |
| e-ISSN | 1873-4251 | |
| Embargo date | 2030-01-01 | |
