Characterization of HIV-1 Enzyme Reverse Transcriptase Inhibition by the Compound 6-Chloro-1,4-Dihydro-4-Oxo-1-(β-D-Ribofuranosyl) Quinoline-3-Carboxylic Acid Through Kinetic and In Silico Studies

Author(s): Thiago Moreno L. Souza, Diego Q. Rodrigues, Vitor F. Ferreira, Isakelly Pereira Marques, Fernanda da Costa Santos, Anna Claudia Cunha, Maria Cecilia Bastos Vieira de Souza, Izabel Christina de Palmer Paixao Frugulhetti, Dumith Chequer Bou-Habib, Carlos Frederico Leite Fontes

Journal Name: Current HIV Research

Volume 7 , Issue 3 , 2009


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Abstract:

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 RTs 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.

Keywords: AIDS, HIV-1, Reverse transcriptase, Chloroxoquinolinic acid

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Article Details

VOLUME: 7
ISSUE: 3
Year: 2009
Page: [327 - 335]
Pages: 9
DOI: 10.2174/157016209788347958
Price: $65

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