The Compound 6-Chloro-1,4-Dihydro-4-Oxo-1-(β-D-Ribofuranosyl) Quinoline-3-Carboxylic Acid Inhibits HIV-1 Replication by Targeting the Enzyme Reverse Transcriptase

Author(s): Thiago Moreno L. Souza, Claudio Cesar Cirne-Santos, Diego Q. Rodrigues, Celina M. Abreu, Amilcar Tanuri, Vitor F. Ferreira, Isakelly Pereira Marques, Maria Cecilia Bastos Vieira de Souza, Carlos Frederico Leite Fontes, Izabel Chistina de Palmer Paixao Frugulhetti, Dumith Chequer Bou-Habib

Journal Name: Current HIV Research

Volume 6 , Issue 3 , 2008

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We describe in this paper that the chloroxoquinolinic ribonucleoside 6-chloro-1,4-dihydro-4-oxo-1-(β-Dribofuranosyl)- quinoline-3-carboxylic acid (compound A) inhibits the HIV-1 replication in human primary cells. We initially observed that compound A inhibited HIV-1 infection in peripheral blood mononuclear cells (PBMCs) in a dosedependent manner, resulting in an EC50 of 1.5 ± 0.5 μM and in a selective index of 1134. Likewise, compound A blocked HIV-1BA-L replication in macrophages in a dose-dependent manner, with an EC50 equal to 4.98 ± 0.9 μM. The replication of HIV-1 isolates from subtypes C and F was also inhibited by compound A with the same efficiency. Compound A inhibited an early event of the HIV-1 replicative cycle, since it prevented viral DNA synthesis in PBMCs exposed to HIV-1. Kinetic assays demonstrated that compound A inhibits the HIV-1 enzyme reverse transcriptase (RT) in dose-dependent manner, with a KI equal to 0.5 ± 0.04 μM. Using a panel of HIV-1 isolates harboring NNRTI resistance mutations, we found a low degree of cross-resistance between compound A and clinical available NNRTIs. In addition, compound A exhibited additive effects with the RT inhibitors AZT and nevirapine, and synergized with the protease inhibitor atazanavir. Our results encourage continuous studies about the kinetic impact of compound A towards different catalytic forms of RT enzyme, and suggest that our nucleoside represents a promising molecule for future antiretroviral drug design.

Keywords: HIV-1, reverse transcriptase, chloroxoquinolinic ribonucleoside, inhibitor

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Article Details

Year: 2008
Page: [209 - 217]
Pages: 9
DOI: 10.2174/157016208784324930
Price: $65

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