Eisaku Tsujii

Discovery of anti-varicella zoster virus activity of polyether antibiotic CP-44161

In search for new anti-varicella zoster virus (VZV) compounds with new mechanism of action, we applied a DNA hybridization assay (dot blot method) for screening. Using this method, we screened microbial products and found the polyether compound CP-44161 from the culture broth of an actinomycete strain. CP-44161 was previously reported as an anticoccidal agent, but there has been no claim of its antiviral activities. CP-44161 showed strong anti-VZV activity against pOka strain by plaque reduction assay. Moreover, CP-44161 showed lower cytotoxicity than other antiviral polyethers, such as monensin and nigericin. Its better safety margin and strong anti-VZV properties make it a good candidate for a new anti-VZV agent.

Anti-herpes virus activity of polyether antibiotic CP-44161 in vivo

In the previous study, we discovered a polyether antibiotic CP-44161, which was reported earlier as an anticoccidal agent, as an anti-varicella zoster virus compound. In this study, we demonstrated that CP-44161 had a very strong and broad anti-herpes virus activities against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in vitro. To determine the antiviral activity of CP-44161 in vivo, we examined its effect on the cutaneous HSV-2 infection model in Balb/c mice. CP-44161 showed inhibitory effect on lesion development as well as acyclovir (ACV) when the treatment was started from day 3. Meanwhile, in case the start of treatment was delayed until day 4, when ACV was no longer effective, the effectiveness of CP-44161 still remained. In this model, CP-44161 also showed inhibitory effect on the proliferation of HSV-2 DNA in dorsal root ganglia. This is the first article to report that polyether antibiotics can be effective on viral infection in vivo.

Effect of WF11605, a novel LTB4 antagonist on galactosamine-induced hepatitis in rats.

The pathogenic mechanism of fulminant hepatitis induced by a 400 mg/kg D-galactosamine was investigated in male Wistar rats. The extent of liver injury was assessed by measurements of serum transaminases, serum total bilirubin and relative liver weight at 24 hr after D-galactosamine administration.WF 11605 is a selective antagonist of leukotriene B4 (LTB4) . The compound was isolated as a product of fungal metabolite. WF 11605 inhibited LTB4-induced chemotaxis of rabbit polymorphonuclear leukocyte (PMN) with an IC50 value of 1.7 × 10-7 M and blocked 3H-LTB4 binding to PMN membrane at 5.6 × 10-6 M (IC50) . WF 11605 also inhibited LTB4-induced degranulation of rabbit PMN at 3.0 × 10-6 M (IC50) . However, the compound did not show any inhibitory effect on platelet activating factor (PAF) -and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) -induced degranulation at concentrations up to 10-4 M. In order to determine whether LTB4 contributes to the occurrence of the hepatitis in rats, we therefore attempted to prevent the hepatitis by WF 11605. Intraperitoneally administered WF 11605 at doses of 10, 32 and 100 mg/kg significantly prevented the increase of serum transaminases and bilirubin in a dose dependent manner. We conclude from our results that LTB4 might be involved in the pathogenesis of D-galactosamine-induced hepatitis in rats.