Foscarnet Sodium

Abstract: Foscarnet (PFA) is a pyrophosphate analogue antiviral active against human immunodeficiency virus (HIV-1) and herpesviruses. Strains of HIV-1 resistant to PFA have mutations in the HIV-1 reverse transcriptase (RT). We examined the influence of PFA resistance mutations, in different genetic backgrounds, on HIV-1 replication competency in both replication kinetics and growth competition assays. In replication kinetics assays, the recombinant strains HX89K, HX92I, and HX156A (encoding RT mutations E89K, L92I, and S156A, respectively, in the HXB2-D genetic background) replicated to lower titers than the wild-type parent in the absence of drug, and the degree of replication impairment increased as PFA resistance increased. PFA-resistant strains LAI 921 and LAI 156A (encoding RT mutations L92I and S156A, respectively) were replication impaired in comparison to the wild-type parent LAI to a similar degree as observed for strains in the HXB2D background. In growth competition assays with wild-type LAI, s...

Abstract: Monoalkyl ether lipid analogues of foscarnet (phosphonoformate, PFA) exhibit substantially greater in vitro antiviral activity than unmodified PFA against human immunodeficiency virus type 1 (HIV-1). Our previous studies indicate that the length of the alkyl chain must be 14-22 carbons for optimal antiviral activity. To further evaluate the structure-activity relationship, we prepared 1-O-octadecyl-sn-glycerol analogues of PFA with various substitutions at the sn-2 position of glycerol and determined the effect of structure on in vitro antiviral activity and selectivity against HIV-1 in MT-2 and CD4-expressing HeLa cells (HT4-6C). We also studied combinations of zidovudine with PFA, 1-O-octadecyl-2-O-methyl-sn-glycero-3-PFA, or 1-O-octadecyl-sn-glycero-3-PFA and calculated their combination index values against HIV-1 in HT4-6C cells. Alkyl substitutions of one to four carbons at the sn-2 position of glycerol showed optimal antiviral activity. Both alkyl ether lipid analogues were strongly synergistic with zidovudine over a wide range of drug ratios and concentrations. 1-O-octadecyl-sn-glycerol analogues of PFA have selective antiviral properties and warrant further evaluation as potential antiretroviral drugs.

Abstract: The efficient in vitro inhibition of hepatitis B virus DNA polymerase by trisodium phosphonoformate (PFA, INN: foscarnet sodium) and its low toxicity suggested that PFA could be used as a therapeutic agent for hepatitis B infection. PFA was also found to inhibit woodchuck hepatitis virus (WHV) DNA polymerase in vitro. As a model to test PFA's eventual effect, chronically WHV infected woodchucks were treated with PFA. The animals were treated twice daily in a dosage which gave a minimum serum level of PFA corresponding to an in vitro inhibiting effect on WHV DNA polymerase of about 40%. The concentration in liver tissue was found to be 15% below serum level. The amount of WHV particles in serum was followed by DNA polymerase assay. No effect on WHV production could be seen during 2 weeks' treatment. No change of the in vitro sensitivity to PFA of the WHV DNA polymerase was seen. These results indicate that the WHV associated DNA polymerase has no role in the production of viral particles.