Inhibition of HSV-1 replication and HSV DNA polymerase by the chloroxoquinolinic ribonucleoside 6-chloro-1,4-dihydro-4-oxo-1-(beta-D-ribofuranosyl) quinoline-3-carboxylic acid and its aglycone.
We describe in this paper that the synthetic chloroxoquinolinic ribonucleoside 6-chloro-1,4-dihydro-4-oxo-1-(beta-D-ribofuranosyl) quinoline-3-carboxylic acid (compound A) and its free aglycogene base (compound B) inhibit, with low cytotoxicity, the replication of herpes simplex virus type 1 and 2 (HSV-1 and HSV-2). Compound A inhibited HSV-1 replication in Vero cells with an EC(50) of 1.3 and 1.4 microM for an acyclovir (ACV)-sensitive strain and an ACV-resistant strain of this virus, respectively. Additionally, it inhibited HSV-2 replication with an EC(50) of 1.1 microM. Compound B also inhibited the ACV-sensitive and -resistant HSV-1 strains, and HSV-2 at EC(50) values of 1.7, 1.9 and 1.6 microM, respectively. Time-of-addition assays, performed with compound A, suggested that this molecule at an early time point of the HSV replication cycle. Kinetic assays demonstrated that compounds A and B inhibit the HSV DNA polymerase activity in a noncompetitive fashion, with a K(i) equal to 0.1 and 0.2 microM, respectively. Taken together, our results suggest that compounds A and B represent promising lead molecules for further anti-HSV drug design.
Souza
Thiago Moreno L
TM
Laboratório de Virologia Molecular, Departamento de Biologia Celular e Molecular, Instituto de Biologia, Universidade Federal Fluminense, Niterói, RJ, Brazil. tmoreno@bioqmed.ufrj.br
De Souza
Maria Cecilia Bastos V
MC
Ferreira
Vitor F
VF
Canuto
Carla Veronica B Santos
CV
Marques
Isakelly Pereira
IP
Fontes
Carlos Frederico L
CF
Frugulhetti
Izabel C P P
IC
D000212:Acyclovir / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D019384:Nucleic Acid Synthesis Inhibitors; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D012263:Ribonucleosides / Q000737:chemistry / Q000494:pharmacology*; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects*
C527872:6-chloro-1,4-dihydro-4-oxo-1-(beta-D-ribofuranosyl)quinoline-3-carboxylic acid; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D011804:Quinolines; D012263:Ribonucleosides; D000212:Acyclovir