Effects of purine nucleoside analogues with a cyclobutane ring and erythromycin A oxime derivatives on duck hepatitis B virus replication in vivo and in cell culture and HIV-1 in cell culture
✍ Scribed by Li-Fang Hung; Amy E. Brumbaugh; Gulshan Bhatia; Patricia L. Marion; Paul P. Hung; Daniel W. Norbeck; Jacob J. Plattner; William S. Robinson
- Publisher
- John Wiley and Sons
- Year
- 1991
- Tongue
- English
- Weight
- 650 KB
- Volume
- 35
- Category
- Article
- ISSN
- 0146-6615
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✦ Synopsis
Abstract
The effects on duck hepatitis B virus (DHBV) replication of specific analogues of two classes of chemical compounds not previously tested against hepadnaviruses are described. One is erythromycin A‐9‐methyloxime (EMO) and other oxime derivatives of erythromycin A, and the other is purine nucleoside analogues (cyclobut A and cyclobut G)with cyclobutane rings. Viral replication was assessed by measuring serum levels of DHBV DNA in infected ducklings and DHBV DNA in infected primary duck hepatocyte cultures.
Administration of EM0 15 mg/kg of body weight IM to infected ducklings resulted in a rapid fall in DHBV DNA levels during therapy and a return to pretreatment levels after EM0 administration was stopped. There was local toxicity at injection sites with muscle necrosis in some animals. When 100 mg/kg EM0 was administered by gastric tube no such viral response was observed. The difference in virus response to EM0 15mgikg IM and 100 mgikg by gastric tube was not due to failure to achieve comparable blood and tissue levels of EM0 administered by the different routes. The results suggest an indirect effect dependent on IM injection of EM0 rather than a direct antiviral effect of the compound.
Administration of cyclobut G or cyclobut A at 70 mg/kg IM led to a rapid reduction of DHBV DNA to undetectable levels in serum, and in only 1 of 4 animals did DHBV DNA became detectable again within 10 days after stopping the drug. lntragastric administration of cyclobut G at 180 mg/kg per day was also associated with rapid reduction of serum DHBV DNA with onset of treatment in all animals, undetectable levels in 4 of 5 animals during therapy, and return to pretreatment levels in all animals after the drug was stopped. There were no apparent toxic effects. In cell culture 1 μM cyclobut A or cyclobut G inhibited virus production by more than twentyfold without apparent toxic effects. The results indicate that cyclobut A and cyclobut G are more active on a molar basis than other compounds tested against DHBV in these models, and they appear to be effective byu the oral route. Cyclobut G was much less active than AZT in inhibiting HIV‐1 in cell culture.