WIN 54954 treatment of mice infected with a diabetogenic strain of group B coxsackievirus

Abstract

The therapeutic efficacy of an experimental antiviral agent, WIN 54954, was evaluated in a mouse model in which infection by coxsackievirus B4 (CVB4) strain E2 was followed by diabetes mellitus. Male CD1 mice (age, 5 weeks) were inoculated with 104 PFU of CVB4. VIN 54954 was administered orally via gavage tube in a dose of either S or 50 mg/kg of body weight per day. Treatment was initiated on the day of inoculation and was continued for 10 days. Control animals received the xanthan gum carrier only. At 3 days postinoculation (p.i.), the mean titer of virus in the pancreas was found to be significantly lower in both the high-dose (P < 0.001) and low-dose (P < 0.05) treatment groups compared with that in the controls. Furthermore, islet histologic abnormalities were significantly less common in the high-dose group (P < 0.02) than in the controls. At 7 weeks p.i., both fasting and 1-h postprandial glucose levels in blood were significantly lower for both the high-dose (P < 0.001) and the low-dose (P < 0.01) treatment groups than in controls. The proportion of mice with persistent viral RNA in the pancreas at this time, as detected by polymerase chain reaction, was significantly reduced in the high-dose treatment group (4 of 11 mice) compared with that in the controls (7 of 8 mice). When mice received 50 mg of WIN 54954 per kg daily beginning at either 48 or 72 h postinoculation, the titers in the pancreas were again significantly reduced at 3 days p.i. compared with those in the controls (P < 0.01 and P < 0.05, respectively). Thus, WIN 54954 effectively reduces virus replication and islet histologic changes acutely and decreases, at 7 weeks, both the metabolic alteration associated with diabetes mellitus and the incidence of detectable viral RNA in the pancreas.

Selective inhibitors of picornavirus replication

“…74 In a murine CVA9-induced myocarditis model, WIN54954 reduced viral replication at 50 mg/kg/day, but caused neurological toxicity at doses of >100 mg/kg/day. 75 The compound was well tolerated in phase I clinical trials, and was effective in humans naturally infected with CVA21, but lacked activity against experimentally induced infections caused by rhinovirus strains 23 and 29.…”

Viral infections in type 1 diabetes mellitus — why the β cells?

“…The availability of drugs targeting different steps of the viral cycle enables combined treatment to avoid viral resistance to the antiviral therapy. Some compounds have shown efficacy to reduce coxsackievirus amplification and to protect pancreatic islets from coxsackievirus-induced cytopathogenic effects 138–141 ; to eradicate the virus in infected pancreatic β cell lines 142 ; and to prevent and/or reduce the incidence of virally-induced diabetes mellitus in mice 140,141 . Adapted antiviral treatment at the pre-diabetic stage could eliminate persistent infection, thus reducing inflammation and the risk of autoimmunity and T1DM.…”

Mutation in Enterovirus 71 Capsid Protein VP1 Confers Resistance to the Inhibitory Effects of Pyridyl Imidazolidinone

“…The clinical studies for disoxaril were discontinued due to the appearance of crystalluria in healthy volunteers at high dosages. Its successors, WIN 54954 (35,36,39) and WIN 61605, were then developed and evaluated. However, neither compound was researched further because of toxicity or low efficacy.…”