Antipoliovirus activity of isothiazole derivatives: mode of action of 5,5'-diphenyl-3,3'-diisothiazole disulfide (DID).
In this report we describe the antiviral activity of 5,5'-diphenyl-3,3'-diisothiazole disulfide (DID) and discuss its mode of action. DID selectively inhibits the replication of poliovirus type 1 (therapeutic index = 255) by affecting some early process of the virus growth cycle. The compound does not interfere with adsorption and internalization of virus to HEp-2 cells, nor with uncoating of the viral RNA. However, no viral RNA synthesis occurs after 2 h post-infection in the presence of 50 microM DID. Thus, we investigated some molecular events in poliovirus replication occurring between uncoating and viral RNA synthesis. In our experimental design, we studied the activity of RNA polymerase complex isolated from HEp-2 infected cells in the presence or absence of DID. Our results showed that the RNA polymerase complex was formed in the presence of DID. On the contrary, DID markedly inhibited poliovirus RNA synthesis in a cell-free system using RNA polymerase complex isolated from infected cells. These findings indicate that DID may exert its antiviral activity by preventing viral RNA chain elongation via the inhibition of replicase activity and/or interfering with viral RNA polymerase complex.
Garozzo
A
A
Institute of Microbiology, University of Catania, Italy.
Pinizzotto
M R
MR
Guerrera
F
F
Tempera
G
G
Castro
A
A
Geremia
E
E
D000998:Antiviral Agents / Q000633:toxicity*; D002213:Capsid / Q000378:metabolism; D002294:Carcinoma, Squamous Cell; D002460:Cell Line; D012321:DNA-Directed RNA Polymerases / Q000187:drug effects / Q000378:metabolism*; D004220:Disulfides / Q000633:toxicity*; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure; D017955:Poliovirus / Q000187:drug effects* / Q000502:physiology; D012367:RNA, Viral / Q000096:biosynthesis; D011991:Receptors, Virus / Q000502:physiology; D013844:Thiazoles / Q000633:toxicity*; D014407:Tumor Cells, Cultured; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D004220:Disulfides; D012367:RNA, Viral; D011991:Receptors, Virus; D013844:Thiazoles; C087420:5,5'-diphenyl-3,3'-diisothiazole disulfide; D012321:DNA-Directed RNA Polymerases