title: The compound 6-chloro-1,4-dihydro-4-oxo-1-(beta-D-ribofuranosyl) quinoline-3-carboxylic acid inhibits HIV-1 replication by targeting the enzyme reverse transcriptase.
abstract: We describe in this paper that the chloroxoquinolinic ribonucleoside 6-chloro-1,4-dihydro-4-oxo-1-(beta-D-ribofuranosyl)-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 dose-dependent manner, resulting in an EC(50) of 1.5 +/- 0.5 microM and in a selective index of 1134. Likewise, compound A blocked HIV-1(BA-L) replication in macrophages in a dose-dependent manner, with an EC(50) equal to 4.98 +/- 0.9 microM. 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 K(I) equal to 0.5 +/- 0.04 microM. 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.
authors.affiliation: Laboratório de Virologia Molecular, Departamento de Biologia Celular e Molecular, Instituto de Biologia,Universidade Federal Fluminense, Niterói, RJ, Brazil.
authors.forename: Thiago Moreno L
authors.initials: TM
authors.lastname: Souza
authors.forename: Claudio Cesar
authors.initials: CC
authors.lastname: Cirne-Santos
authors.forename: Diego Q
authors.initials: DQ
authors.lastname: Rodrigues
authors.forename: Celina M
authors.initials: CM
authors.lastname: Abreu
authors.forename: Amílcar
authors.initials: A
authors.lastname: Tanuri
authors.forename: Vitor F
authors.initials: VF
authors.lastname: Ferreira
authors.forename: Isakelly Pereira
authors.initials: IP
authors.lastname: Marques
authors.forename: Maria Cecilia Bastos Vieira
authors.initials: MC
authors.lastname: de Souza
authors.forename: Carlos Frederico Leite
authors.initials: CF
authors.lastname: Fontes
authors.forename: Izabel Chistina de Palmer Paixão
authors.initials: IC
authors.lastname: Frugulhetti
authors.forename: Dumith Chequer
authors.initials: DC
authors.lastname: Bou-Habib
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000821:virology; D011804:Quinolines / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D012263:Ribonucleosides / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: C527872:6-chloro-1,4-dihydro-4-oxo-1-(beta-D-ribofuranosyl)quinoline-3-carboxylic acid; D019380:Anti-HIV Agents; D011804:Quinolines; D018894:Reverse Transcriptase Inhibitors; D012263:Ribonucleosides; D054303:HIV Reverse Transcriptase