Antiviral activities of ribavirin, 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide, and 6'-(R)-6'-C-methylneplanocin A against several ortho- and paramyxoviruses

Abstract

5-Ethynyl-l-o-D-ribofuranosylimidazole-4-carboxamide (EICAR) and 6'-(R)-6'-C-methylneplanocin A (TJ13025) are two novel antiviral agents which are targeted against IMP dehydrogenase and S-adenosylhomocysteine hydrolase, respectively. These compounds have been examined for their activities against various strains of orthomyxoviruses (influenza virus) and paramyxoviruses (parainfluenza virus, mumps virus, measles virus, and respiratory syncytial virus) in vitro. EICAR was 10-to 59-fold more active than ribavirin and TJ13025 was 32-to 330-fold more active than ribavirin against parainfluenza virus (types 2 and 3), mumps virus, and measles virus. EICAR was also more active than ribavirin against respiratory syncytial virus and influenza virus, whereas TJ13025 was virtually inactive against these viruses. The 50% virus-inhibitory concentrations of EICAR and TJ13025 were generally within the 0.1-to 1-,ug/ml range. Although the compounds did not prove cytotoxic to stationary host cells (HeLa, Vero, MDCK, and LLCMK2) at a concentration of 200 ,ug/ml, concentrations of 4 to 13 ,ug/ml inhibited the growth of dividing cells. EICAR and TJ13025 should be further pursued as candidate drugs for the treatment of ortho-and paramyxovirus infections.Ribavirin has been licensed for clinical use (as an aerosol) in the treatment of respiratory syncytial virus (RSV) infections. Inhalation of aerosolized ribavirin by infants with RSV pneumonia or college students with influenza A leads to an improvement of the clinical symptoms in these patients (7,19,20). The mechanism of action of ribavirin and its metabolism by cells have been investigated (5,6,17,18,21); the main targets for the antiviral action of ribavirin and its phosphorylated form appear to be IMP dehydrogenase, viral mRNA cap formation, and viral RNA transcriptase or polymerase.Recently, we have reported two novel nucleoside analogs, 5 -ethynyl -1-, -D -ribofuranosylimidazole -4 -carboxamide (EICAR) and 6'-(R)-6'-C-methylneplanocin A (TJ13025), as broad-spectrum antiviral agents active against a wide variety of pox-, toga-, reo-, myxo-, rhabdo-, and arenaviruses in vitro (3,16). In this study, we have evaluated the inhibitory effects of EICAR and TJ13025 in comparison with those of ribavirin on the in vitro replication of several ortho-and paramyxoviruses. MATERIALS AND METHODSCompounds. The sources of the three compounds used in this study were as follows: ribavirin, ICN Pharmaceuticals,

A Colorimetric LDH Assay for the Titration of Infectivity and the Evalution of Anti-Viral Activity against Ortho- and Paramyxoviruses.

“…Using the LDH method, ribavirin and EICAR showed lower values of the EC50 against FLUV-A, C, PFLUV and MPSV than those obtained by the PR method with monolayers of Vero, LLC-MK2, HeLa and MDCK cells (Shigeta et al 1992a). The EC50 values of ribavirin and EICAR by the LDH method were lower than those derived with the MTT method and in case of FLUV-C, PFLUV-1 and 3, the EC50 values were not obtained by the MTT method.…”

“…For anti-viral activity and cytotoxicity by MTT and PR methods, we followed methods described previously (Pauwels et al 1988;Takeuchi et al 1991;Shigeta et al 1992a). …”

Inhibitory Effect of a Nucleotide Analog on Infectious Salmon Anemia Virus Infection

“…Ribavirin has proven to be an inhibitor of several ortho-and paramyxoviruses (42). Furthermore, ribavirin inhibits in vitro and in vivo replication of influenza virus (15,33,49,50), the most typical member of the Orthomyxoviridae family.…”

Severe Measles Pneumonitis in Adults

“…The mortality among patients with MDRTB has ranged from 72% to 89%, and the median interval between the diagnosis of MDRTB and death has been short, ranging from 4 to 6 weeks [3].…”

“…The case of patient 2 demonstrates that severe measles pneumonitis in immunocompetent adults, even when intubation and mechanical ventilation are required, can have a favorable course in the absence of specific therapeutic measures. Despite some evidence for an effect ofribavarin in patients with measles [3,4], the drug's value in adults has yet to be convincingly demonstrated. Porter et al noted that <30 cases of tuberculous bronchoesophageal fistulae (BEF) have been reported in the literature, and they described three additional patients who were infected with HIV [2].…”