Gliotoxin

Gliotoxin is an immunosuppressive mycotoxin produced by pathogenic strains of Aspergillus and other fungi with diverse biological activities.[1],[2],[3],[4],[5],[6],[7],[8] It inhibits 20S proteasomal chymotrypsin activity (IC50 = 10 μM), blocking the degradation of IκBα and preventing the activation of NF-κB.[2],[3] Gliotoxin induces apoptosis in monocytes and dendritic cells and reduces phagocytosis by neutrophils.[4],[5]It suppresses viral infection by Nipah and Hendra virus in HEK293T cells (IC50s = 149 and 579 nM, respectively).[6] Under reducing conditions, gliotoxin inhibits leukotriene A4 hydrolase epoxide hydrolase activity, but not aminopeptidase activity, and leukotriene B4 synthesis in neutrophils and monocytes.[7] In vivo, gliotoxin (5 mg/kg) reduces LTB4 plasma levels and blocks peritoneal neutrophil infiltration in a mouse model of peritonitis induced by zymosan A. It also inhibits geranylgeranyltransferase I and farnesyltransferase (IC50s = 17 and 80 μM, respectively).[8]

Reference:
[1]. Kwon-Chung, K.J., and Sugui, J.A. What do we know about the role of gliotoxin in the pathobiology of Aspergillus fumigatus? Med. Mycol. 47(Suppl 1), S97-S103 (2009).
[2]. Kroll, M., Arenzana-Seisdedos, F., Bachelerie, F., et al. The secondary fungal metabolite gliotoxin targets proteolytic activities of the proteasome. Chem. Biol. 6(10), 689-698 (1999).
[3]. Pahl, H.L., Krauss, B., Schulze-Osthoff, K., et al. The immunosuppressive fungal metabolite gliotoxin specifically inhibits transcription factor NF-κB. J. Exp. Med. 183(4), 1829-1840 (1996).
[4]. Anselmi, K., Stolz, D.B., Nalesnik, M., et al. Gliotoxin causes apoptosis and necrosis of rat Kupffer cells in vitro and in vivo in the absence of oxidative stress: Exacerbation by caspase and serine protease inhibition. J. Hepatol. 47(1), 103-113 (2007).
[5]. Orciuolo, E., Stanzani, M., Canestraro, M., et al. Effects of Aspergillus fumigatus gliotoxin and methylprednisolone on human neutrophils: Implications for the pathogenesis of invasive aspergillosis. J. Leukoc. Biol. 82(4), 839-848 (2007).
[6]. Aljofan, M., Sganga, M.L., Lo, M.K., et al. Antiviral activity of gliotoxin, gentian violet and brilliant green against Nipah and Hendra virus in vitro. Virol. J. 6:187, (2009).
[7]. König, Pace, S., Pein, H., et al. Gliotoxin from Aspergillus fumigatus abrogates leukotriene B4 formation through inhibition of leukotriene A4 hydrolase. Cell. Chem. Biol. 26(4), 524-534 (2019).
[8]. Vigushin, D.M., Mirsaidi, N., Brooke, G., et al. Gliotoxin is a dual inhibitor of farnesyltransferase and geranylgeranyltransferase I with antitumor activity against breast cancer in vivo. Med. Oncol. 21(1), 21-30 (2004).