| Autor: |
Souza, Thiago Moreno L., Rodrigues, Diego Q., Ferreira, Vitor F., Marques, Isakelly Pereira, Santos, Fernanda da Costa, Cunha, Anna Claudia, de Souza, Maria Cecilia Bastos Vieira, Paixao Frugulhetti, Izabel Christina de Palmer, Bou-Habib, Dumith Chequer, Fontes, Carlos Frederico Leite |
| Zdroj: |
Current HIV Research; May 2009, Vol. 7 Issue: 3 p327-335, 9p |
| Abstrakt: |
We recently described that the chloroxoquinolinic ribonucleoside 6-chloro-1,4-dihydro-4-oxo-1-(β-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. |
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