Brefeldin A (decumbin, "BFA") was first isolated in 1958 as a fungal metabolite from Penicillium decumbens (Singleton, V. L., et al., Nature 181:1072-1073 (1958)). BFA has a molecular weight of 280.37 (C.sub.16 H.sub.24 O.sub.4) and reportedly has a wide range of biological activities, including antifungal, antiviral and antitumor effects. See Betina, Folia Microbiol. 37(1):3-11 (1992) for a recent review. At the cellular level, BFA has dramatic effects on the secretory pathway and protein trafficking in mammalian cells. (Pelham, H. R. B., Cell, 67:449-451 (1991); (Klausner, R. D., et al., J. Cell Biol., 116:1071-1080 (1992)). BFA has been shown to also inhibit protein transport in fungi, such as Candida albicans (Arioka, M., et al., J. Gen. Microbiol., 137:1253-1262 (1991)) and inhibit the presentation of endogenous and exogenous protein antigens by MHC class II-restricted T-cells (Adorini, L., et al., Nature, 246:63-66 (July 1990)). BFA has also been shown to have selective cytotoxic activity against human tumor cell lines (Ishii, S., et al., J. Antibiot., XLII:1877-1878 (1989)).
BFA also inhibits virus replication by interfering with the intracellular transport and maturation of viral proteins. Inhibition, as defined herein, means a significant reduction in virus particle replication, as well as complete abrogation of virus particle replication. Enveloped viruses, such as herpes viruses (including Herpes Simplex) and Human Immunodeficiency Virus (HIV), require the host cell secretory apparatus for transport and processing of envelope (membrane) glycoproteins during the course of virus assembly and maturation. BFA has also been shown to inhibit infectious viral particle formation by preventing the transport of envelope glycoprotein to the cell surface as required for assembly of mature, infectious viral particles. (Cheung, P., et al., J. Virol., 65:1893-1904 (1991); Pal, R., et al., Aids Res. Human Retroviruses, 7:707-712 (1991); see also Takatsuki et al, Agric. Biol. Chem. 49(3):899-902 (1985)).
BFA has a short biological half-life. It is rapidly deactivated in vivo via conjugation with glutathione by glutathione S-transferase and subsequently transported out of the cell (Bruning, A., et al., J. Biol. Chem., 267:7726-7732 (1992)). Compounds having some or all of the biological activities of BFA combined with an extended useful biological half-life and/or improved overall therapeutic profiles would be valuable for the treatment of viral, bacterial, fungal and other diseases, as anti-cancer agents, as immunosuppresive agents and as detoxifying agents.
USPTO Backgrounds
USPTO Backgrounds