In vitro activity of WIN 51711, a new broad-spectrum antipicornavirus drug

Abstract

WIN 51711 (5-[7-[4-(4,5-dihydro-2-oxazolyl)phenoxy]heptyl]-3-methylisoxazole), a new antipicornavirus drug, is a potent inhibitor of human entero-and rhinoviruses at concentrations not inhibitory to HeLa cell growth. In plaque reduction assays, WIN 51711 reduced plaque formation by 9 enteroviruses and 33 rhinoviruses, with MICs of 0.004 to 0.17 and 0.004 to 6.2 p,g/ml, respectively. Addition of WIN 51711 to infected cells at concentrations of 0.02 to 5.0 ,ug/ml reduced the yield of picornaviruses by 90%. Other RNA viruses (nonpicornaviruses) and DNA viruses were unaffected by the compound.Currently, no drugs are available for the treatment of human diseases caused by the rhino-and enterovirus members of the picornavirus family (7). Based on the finding that arildone is a potent inhibitor of a limited number of enteroviruses in vitro (1, 2) and in vivo (4), a series of analogs was synthesized in an effort to discover a systemically active compound with broad-spectrum activity against the causative agents of viral meningitis, hepatitis A, acute hemorrhagic conjunctivitis, and the common cold (6, 9). This report describes the potent in vitro activity of WIN 51711 ( Fig. 1)

Prevention of rhinovirus and poliovirus uncoating by WIN 51711, a new antiviral drug

“…However, the majority of the 33 serotypes which were tested showed a 50% reduction in plaque formation at less than 1 ,ug of WIN 51711 per ml (2.9 ,uM). Similar results were reported in virus yield reduction studies (10). WIN 51711 has also been shown to be systemically active in the prevention of paralysis and death in mice infected with human poliovirus type 2 (8) 433,1984).…”

“…3. The WIN 51711 concentrations effective in preventing uncoating were similar to the concentrations previously shown to inhibit virus replication as measured by virus yield (10).…”

“…In the uncoating assay, the infectivity of neutral red-encapsidated rhinovirus and poliovirus in cells infected in the presence of WIN 51711 was inactivated by exposure to light at 3 h after infection. In addition, the concentrations of WIN 51711 which inhibited uncoating were in the same range as those resulting in a reduction in virus yield (10). The marked inhibitory effects of WIN 51711 on the uncoating of neutral red-encapsidated rhinovirus and poliovirus, and the fact that WIN 51711 reduces virus yield at the same concentrations that affect uncoating, provide evidence that the uncoating step is the major site of activity of this compound.…”

“…3) and caused a 99.9% reduction in virus yield (10). The dose-dependent reduction in infectious centers observed in cultures not exposed to antisera may be caused by inefficient removal of drug from cells, resulting in a partial inhibition of uncoating.…”

“…WIN 51711 was not virucidal, since exposure of rhinovirus and poliovirus to 100 to 10,000 times the reported effective concentration had no effect on virion infectivity (10). WIN 51711 also had no effect on the adsorption of rhinovirus and poliovirus to host cells as measured by the kinetics of [3H]uridine-labeled virus bound to cells in the presence or absence of drug.…”