tetano
Editor, Senior Moderator
Antivir Chem Chemother. 2012 Apr 19. doi: 10.3851/IMP2105. [Epub ahead of print]
D282, a Non-Nucleoside Inhibitor of Influenza Virus Infection that Interferes with De Novo Pyrimidine Biosynthesis.
Smee DF, Hurst BL, Day CW.
Source
. don.smee@usu.edu.
Abstract
BACKGROUND:
The discovery of novel influenza virus inhibitors remains an important priority in light of the emergence of drug-resistant viruses. Toward this end, a library of over 6000 compounds was tested for antiviral activity.
METHODS:
Strains of influenza virus were evaluated in cytopathic effect (CPE) inhibition and virus yield reduction assays. Intracellular nucleoside triphosphate pools were analyzed by SAX HPLC. Dihydroorotate dehydrogenase inhibition assays were conducted. Influenza virus-infected mice were treated for 5 days with D282.
RESULTS:
A non-nucleoside, 4-[(4-butylphenyl)amino]-2-methylene-4-oxo-butanoic acid (D282), was discovered that inhibited influenza A and B virus CPE by 50% at 6-31 ?M (giving selectivity indices of >13 to >67, based on cytotoxicity of >400 ?M in stationary cell cultures). Ribavirin (positive control) was active at 14-44 ?M (yielding selectivity indices of >9 to >29, with >400 ?M toxicity). D282 and ribavirin inhibited virus yield by 90% at 9.5?3.3 and 10.8?3.2 ?M, respectively. The antiviral activity of D282 in vitro was reversed by addition of uridine, cytidine, and orotic acid. D282 exhibited an uncompetitive inhibition of mouse liver dihydroorotate dehydrogenase (Ki of 2.3?0.9 ?M, Km of 150?16 ?M). Because cellular pyrimidine biosynthesis was inhibited, D282-treated cells had decreased uridine triphosphate and cytidine triphosphate levels. D282 (<100 mg/kg/day) failed to prevent death of mice infected with influenza.
CONCLUSIONS:
D282 was active against influenza A and B viruses by inhibiting de novo pyrimidine biosynthesis. Although effective in vitro, the compound, like others in its class, was devoid of antiviral activity in infected mice.
PMID:
22516927
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/22516927
D282, a Non-Nucleoside Inhibitor of Influenza Virus Infection that Interferes with De Novo Pyrimidine Biosynthesis.
Smee DF, Hurst BL, Day CW.
Source
. don.smee@usu.edu.
Abstract
BACKGROUND:
The discovery of novel influenza virus inhibitors remains an important priority in light of the emergence of drug-resistant viruses. Toward this end, a library of over 6000 compounds was tested for antiviral activity.
METHODS:
Strains of influenza virus were evaluated in cytopathic effect (CPE) inhibition and virus yield reduction assays. Intracellular nucleoside triphosphate pools were analyzed by SAX HPLC. Dihydroorotate dehydrogenase inhibition assays were conducted. Influenza virus-infected mice were treated for 5 days with D282.
RESULTS:
A non-nucleoside, 4-[(4-butylphenyl)amino]-2-methylene-4-oxo-butanoic acid (D282), was discovered that inhibited influenza A and B virus CPE by 50% at 6-31 ?M (giving selectivity indices of >13 to >67, based on cytotoxicity of >400 ?M in stationary cell cultures). Ribavirin (positive control) was active at 14-44 ?M (yielding selectivity indices of >9 to >29, with >400 ?M toxicity). D282 and ribavirin inhibited virus yield by 90% at 9.5?3.3 and 10.8?3.2 ?M, respectively. The antiviral activity of D282 in vitro was reversed by addition of uridine, cytidine, and orotic acid. D282 exhibited an uncompetitive inhibition of mouse liver dihydroorotate dehydrogenase (Ki of 2.3?0.9 ?M, Km of 150?16 ?M). Because cellular pyrimidine biosynthesis was inhibited, D282-treated cells had decreased uridine triphosphate and cytidine triphosphate levels. D282 (<100 mg/kg/day) failed to prevent death of mice infected with influenza.
CONCLUSIONS:
D282 was active against influenza A and B viruses by inhibiting de novo pyrimidine biosynthesis. Although effective in vitro, the compound, like others in its class, was devoid of antiviral activity in infected mice.
PMID:
22516927
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/22516927