Broad-spectrum activity of 8-chloro-7-deazaguanosine against RNA virus infections in mice and rats.
A novel nucleoside analog, 8-chloro-7-deazaguanosine (8-Cl-7-dzGuo), was evaluated for anti-RNA virus activity in rodents in parallel with the related compound 7-deaza-7-thia-8-oxoguanosine (7-dzTOGuo). Half-daily intraperitoneal (i.p.) doses of each substance administered 24 and 18 h prior to i.p. virus challenge protected the majority of mice infected with banzi, encephalomyocarditis, San Angelo, and Semliki Forest viruses at doses of 25, 50 and 100 mg/kg/day. These compounds at 100 mg/kg/day also protected most suckling rats infected intranasally with rat coronavirus. However, no survival benefit was afforded to treated mice infected intranasally with vesicular stomatitis virus. 8-Cl-7-dzguo was orally active against Semliki Forest virus in mice at 200 and 400 mg/kg/day, whereas 7-dzTOGuo is reported to not be effective orally. In uninfected mice, the two compounds induced similar amounts of interferon following i.p. injections. Interferon was induced by oral treatments with 8-Cl-7-dzGuo but not with 7-dzTOGuo. Fifty percent acute lethal doses to uninfected mice treated i.p. in half-daily doses for one day with 7-deazaguanosine (7-dzGuo), 7-dzTOGuo, and 8-Cl-7-dzGuo were 400, 600 and > 1600 (no mortality at this dose) mg/kg/day, respectively. Daily, i.p. treatments for 14 days with these substances (100 mg/kg/day) showed 7-dzGuo as 100% lethal and the other two substances as not toxic. By virtue of reduced toxicity and oral bioavailability, 8-Cl-7-dzGuo appears to have the greatest clinical potential as an interferon-inducing antiviral agent.
Smee
D F
DF
ICN Nucleic Acid Research Institute, Costa Mesa, CA 92626, USA.
Alaghamandan
H A
HA
Ramasamy
K
K
Revankar
G R
GR
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D006151:Guanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D012328:RNA Viruses / Q000187:drug effects*; D051381:Rats; D014777:Virus Diseases / Q000188:drug therapy*
C094455:8-chloro-7-deazaguanosine; D000998:Antiviral Agents; D006151:Guanosine; C061136:isatoribine