In Vitro Antiviral Activity of Mycophenolic Acid and Its Reversal by Guanine-Type Compounds

Abstract

With the agar diffusion test and BS-C-1 cells, mycophenolic acid was found to give a straight-line dose-response activity in inhibiting the cytopathic effects of vaccinia, herpes simplex, and measles viruses. Plaque tests have shown 100% reduction of virus plaques by mycophenolic acid over drug ranges of 10 to 50 μg/ml and virus input as high as 6,000 plaque-forming units (PFU) per flask. Back titration studies with measles virus inhibited by mycophenolic acid have indicated that extracellular virus titers were reduced by approximately 3 logs 10 and total virus was reduced by 1 log 10 . The agar diffusion test system lends itself readily to drug reversal studies. Mycophenolic acid incorporated into agar at 10 μg/ml gave 100% protection to virus-infected cells. Filter paper discs impregnated with selected chemical agents at concentrations of 1,000 μg/ml (20 μg per filter paper disc) were placed on the agar surface. Reversal of the antiviral activity of mycophenolic acid was indicated by virus breakthrough in those cells in close proximity to the filter paper disc. Chemicals showing the best reversal of the antiviral activity of mycophenolic acid were guanine, guanosine, guanylic acid, deoxyguanylic acid, and 2,6-diaminopurine. The reversal of antiviral activity was confirmed by titrations of virus produced with various amounts of both mycophenolic acid and guanine present and by isotope tracer methods with uptakes of labeled uridine, guanine, leucine, and thymidine in treated and nontreated, infected and noninfected cells as parameters. All antiviral effects of mycophenolic acid at 10 μg/ml could be reversed to the range shown by untreated controls by the addition of 10 μg/ml of those chemicals exhibiting reversal activity.

Mycophenolic Acid: A One Hundred Year Odyssey from Antibiotic to Immunosuppressant

“…also had significant antiviral activity . The in vitro antiviral activity was reversed by guanine, guanosine, GMP, and deoxyGMP. , …”

“…52 The in vitro antiviral activity was reversed by guanine, guanosine, GMP, and deoxy-GMP. 48,51 Moreover, MPA inhibited growth of several transplantable murine solid tumors. Of particular note was marked inhibition of the rapidly growing and metastasizing Mecca-lymphosarcoma tumor.…”

“…Beginning in 1968, it had been observed that the antiviral activity of MPA was reversed by compounds such as guanine, guanosine, and GMP. 48,51 It was suggested that MPA might inhibit cellular function by affecting "an essential guanosine metabolic process". 48 Early in 1969, MPA was shown to be a potent inhibitor of nucleic acid biosynthesis in the "L" strain of fibroblasts; the inhibition was reversed by guanine but not hypoxanthine, adenine, or xanthine.…”

“…Beginning in 1968, biological activities were discovered in addition to the antibacterial and antifungal actions. Broth from growth of a strain of Penicillium stoloniferum had antiviral and antitumor properties, and the responsible agent was identified as MPA. ,, The antiviral properties were observed at low concentrations in a monkey kidney cell line against vaccinia, measles, Herpes simplex, and Newcastle disease viruses, but there was no significant in vivo activity against vaccinia, Herpes simplex, and influenza virus in mice. Oral administration of MPA to chickens inhibited development of the Rous sarcoma virus (94% inhibition with 0.125% MPA in the diet) and to a lesser extent splenomegaly in Friend virus infected DBA 2 mice.…”

Antiviral drug discovery: broad-spectrum drugs from nature

“…174 MPA was rst observed to limit the cytopathic effects of VV, HSV and MV in cell cultures. 175 Since then, the drug has been reported to inhibit the replication of Hantaan River virus, DENV, WNV, HBV, HEV, HCV, HIV and poxviruses by affecting viral nucleic acid synthesis. [176][177][178][179][180][181][182] In vivo MPA alone is not effective against HSV, but it has been shown to enhance the anti-HSV activities of acyclovir, gancyclovir and pencyclovir in experimental animal studies.…”