Abstract
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
Current HIV Research
Title: 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
Volume: 6 Issue: 3
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 and Dumith Chequer Bou-Habib
Affiliation:
Keywords: HIV-1, reverse transcriptase, chloroxoquinolinic ribonucleoside, inhibitor
Abstract: 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.
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Souza L. Thiago Moreno, Cirne-Santos Cesar Claudio, Rodrigues Q. Diego, Abreu M. Celina, Tanuri Amilcar, Ferreira F. Vitor, Marques Pereira Isakelly, Bastos Vieira de Souza Cecilia Maria, Leite Fontes Frederico Carlos, de Palmer Paixao Frugulhetti Chistina Izabel and Bou-Habib Chequer Dumith, 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, Current HIV Research 2008; 6 (3) . https://dx.doi.org/10.2174/157016208784324930
DOI https://dx.doi.org/10.2174/157016208784324930 |
Print ISSN 1570-162X |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4251 |
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Management of HIV: Management of HIV: old challenges and new needs
The aim of this thematic issue is to provide the most recent updates regarding the effective management of HIV infection. Antiretroviral therapy (ART) has significantly decreased HIV-related mortality, leading to an enhancement in the quality of life and life expectancy for people living with HIV (PLWH). Despite the numerous advancements ...read more
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