Mycophenolate mofetil inhibits hepatitis C virus replication in human hepatic cells

Abstract

Hepatitis C virus (HCV) infection is the most common indication for liver transplantation and the major cause of graft failure. A widely used immunosuppressant, cyclosporine A (CsA), for people who receive organ transplantation, has been recognized to have the ability to inhibit HCV replication both in vivo and in vitro. In this study, we investigated the effects of several other immunosuppressants, including mycophenolate mofetil (MMF), rapamycin and FK506, on HCV replication in human hepatic cells. MMF treatment of hepatic cells before or during HCV infection significantly suppressed full cycle viral replication, as evidenced by decreased expression of HCV RNA, protein and production of infectious virus. In contrast, rapamycin and FK506 had little effect on HCV replication. Investigation of the mechanism(s) disclosed that the inhibition of HCV replication by MMF was mainly due to its depletion of guanosine, a purine nucleoside crucial for synthesis of guanosine triphosphate, which is required for HCV RNA replication. The supplement of exogenous guanosine could reverse most of anti-HCV effect of mycophenolate mofetil. These data indicate that MMF, through the depletion of guanosine, inhibits full cycle HCV JFH-1 replication in human hepatic cells. It is of interest to further determine whether MMF is indeed beneficial for HCV-infected transplant recipients in future clinical studies.

Mycophenolic acid, an immunomodulator, has potent and broad-spectrum in vitro antiviral activity against pandemic, seasonal and avian influenza viruses affecting humans

“…MPA is a non-competitive reversible inhibitor of IMDPH, which is an enzyme involved in the cellular biosynthesis of purine mononucleotides (Villarroel et al, 2009). MPA has broad-spectrum antiviral activity against both DNA and RNA viruses (Chan et al, 2013a;Chapuis et al, 2000;Cline et al, 1969;Diamond et al, 2002;Khan et al, 2011;Sebastian et al, 2011;Wang et al, 2014b;Ye et al, 2012), and guanosine depletion has been found to contribute to antiviral activity for several of these viruses.…”

Attenuation of vesicular stomatitis virus infection of brain using antiviral drugs and an adeno-associated virus-interferon vector

“…The 12 compounds tested were chosen based on their previously reported antiviral effects on peripheral or CNS infection of VSV or related viruses: IFN (Detje et al, 2009; Wollmann, Robek, and van den Pol, 2007), ribavirin (Toltzis and Huang, 1986; Willoughby et al, 2005), octyl gallate (Yamasaki et al, 2007), mycophenolic acid (MPA) (Ye et al, 2012), dansylcadaverine (Schlegel et al, 1982), rimantadine (Kolocouris et al, 1996), amantadine (Schlegel et al, 1982; Superti et al, 1985; Willoughby et al, 2005), adenine 9-β-D-arabinofuranoside (Ara-a) (Grant and Sabina, 1972), chloroquine (Dille and Johnson, 1982), acetylsalicylic acid (aspirin) (Chen, Warner, and Reiss, 2000), adenosine (Schnitzlein and Reichmann, 1980), and S-Nitroso-N-acetylpenicillamine (SNAP) (Bi and Reiss, 1995). These drugs act by a variety of mechanisms including interfering with RNA metabolism and replication via nucleoside analogues (ribavirin, Ara-A) or non-nucleoside inhibitors (mycophenolic acid), delaying of viral replication (octyl gallate), inhibition of virus internalization and uncoating (dansylcadaverine, amantadine, rimantadine), G-protein processing (chloroquine), and nitric oxide supply (SNAP).…”

Discovering novel anti-HCV compounds with inhibitory activities toward HCV NS3/4A protease

“…Ribavirin showed neither anti-HCV activity nor a protease inhibitory effect when it was used without IFN-α. The inhibi- npg tion of HCV replication by mycophenolic acid (MPA) was primarily due to its depletion of guanosine, which is required for viral RNA synthesis [24] ; therefore, it was inactive in the HCV NS3/4A protease assay. The reference compound, VX-950, was the only compound that was active in all three systems as a HCV NS3/4A protease inhibitor.…”