Therapy of experimental influenza virus infection with pyrrolidine dithiocarbamate

Abstract

The search for new antiviral strategies to treat influenza A virus (IAV) infections is one major international health care activity. Hereby, the IAV-caused misuse of cellular nuclear factor kappa B (NF-κB) signaling pathways in infected cells represents one target for antiviral therapy. In the present study, pyrrolidine dithiocarbamate (PDTC), which is known as an antioxidant and as an inhibitor of IAV-induced NF-κB activation, was studied in vivo. After the antiviral activity of PDTC was confirmed in MDCK cells, mice-infected with the mouse-adapted strain of IAV A/PR/8/34 (H1N1)-were treated intraperitoneally simultaneously with PDTC (75, 150, 200 mg/kg body weight). The influence of PDTC administrations was evaluated on viral replication and inflammatory reactions in lung tissue up to 14 days postinfection (p. i.). This therapy increased survival up to 80% and reduced IAV-caused weight loss and viral replication in lung tissue in a dose-dependent manner. Protective effects were less pronounced, if the therapy started later on during an ongoing IAV infection. In addition, simultaneous PDTC treatment also limited IAV-caused infiltration of immune cells as well as local interferon-γ expression in lung tissue. These results imply that PDTC decreases IAV-caused disease in mice significantly. Therefore, the development of drugs like PDTC that interfere with NF-κB signaling may represent a modern focus of anti-IAV therapy.

Pyrrolidine dithiocarbamate inhibits enterovirus 71 replication by down-regulating ubiquitin–proteasome system

“…PDTC, an antioxidant and radical scavenger, has been shown to possesses antiviral activity against CVB3, influenza virus, rhinovirus, and herpes simplex virus (Krenn et al, 2005;Lanke et al, 2007;Qiu et al, 2013;Si et al, 2005;Wiesener et al, 2011). In this study, we found that PDTC could inhibit viral RNA synthesis, viral protein expression, and the overall virus yield of EV71.…”

“…Pyrrolidine dithiocarbamate (PDTC) is a synthetic compound, which is largely used as antioxidant or nuclear factor kappa B (NF-B) inhibitor (Morais et al, 2010;Wiesener et al, 2011;Yucel et al, 2013). Previous studies have shown that PDTC could inhibit the replication of coxsackievirus B3 (CVB3), rhinovirus, influenza virus, and herpes simplex virus (Krenn et al, 2005;Qiu et al, 2013;Si et al, 2005;Uchide and Ohyama, 2003;Uchide et al, 2002;Wiesener et al, 2011), while the precise mechanism involved in the antiviral activity of PDTC has not been elucidated.…”

“…Previous studies have shown that PDTC could inhibit the replication of coxsackievirus B3 (CVB3), rhinovirus, influenza virus, and herpes simplex virus (Krenn et al, 2005;Qiu et al, 2013;Si et al, 2005;Uchide and Ohyama, 2003;Uchide et al, 2002;Wiesener et al, 2011), while the precise mechanism involved in the antiviral activity of PDTC has not been elucidated. The inhibited replication of CVB3 and mengovirus by the treatment of PDTC was associated with the transportation of zinc ions into the cells (Lanke et al, 2007;Si et al, 2005).…”

The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design

“…Three other NF‐ κ B inhibitors, pyrrolidine dithiocarbamate , SC75741 , and Bay 11–7082 (Fig. C), were reported to significantly decrease influenza virus‐induced disease in mice …”

New treatments for influenza

“…Thus, inhibitors of NF-κB may have a two-pronged beneficial effect in influenza: they will inhibit the virus directly and will also moderate the systemic inflammation. This has been shown in cell culture and mice [84-86], but specific and controlled studies in patients with influenza still need to be done. Nonetheless, the prospects of an anti-inflammatory therapy of influenza are real, because some anti-NF-κB drugs, such as acetyl salicylate (aspirin) are routinely sold in stores without prescription and widely used by the general public for many years without major side effects.…”