Abstract
Picornaviridae represent a very large family of small RNA viruses, some of which are the cause of important human and animal diseases. Since no specific therapy against any of these viruses currently exists, palliative symptomatic treatments are employed. The early steps of the picornavirus replicative cycle seem to be privileged targets for some antiviral compounds like disoxaril and pirodavir. Pirodavir’s main weakness is its cytotoxicity on cell cultures at relatively low doses. In this work some original synthetic compounds were tested, in order to find less toxic compounds with an improved protection index (PI) on infected cells. Using an amino group to substitute the oxygen atom in the central chain, such as that in the control molecule pirodavir, resulted in decreased activity against Rhinoviruses and Polioviruses. The presence of an -ethoxy-propoxy- group in the central chain (as in compound I-6602) resulted in decreased cell toxicity and in improved anti-Rhinovirus activity. This compound actually showed a PI >700 on HRV14, while pirodavir had a PI of 250. These results demonstrate that modification of pirodavir’s central hydrocarbon chain can lead to the production of novel derivatives with low cytotoxicity and improved PI against some strains of Rhinoviruses.
Highlights
The viruses in the Picornaviridae family cause an extraordinarily wide range of illnesses [1,2,3,4]
Other “capsid-binding” compounds are pirodavir and its derivatives, which have proved to be effective in intranasal treatment of patients with a common cold caused by some strains of human Rhinoviruses [18]
Substance I-6501 showed a protection index (PI) of 4 on HRV14 and of 40 on HRV39, whereas compounds I-6502, I-6602 and I-6702 were the most active antiRhinovirus molecules tested in this study; I-6502 scored a PI of 83 on HRV14 and of 178 on HRV39; I-6602 showed an effective dose of 0.07 μg/mL on HRV14 and HRV39, with a PI of 714 on both virus strains
Summary
The viruses in the Picornaviridae family cause an extraordinarily wide range of illnesses [1,2,3,4]. RNA from degradation by environmental RNAse, (b) selecting and packaging viral RNA, (c) penetrating target cells and delivering the viral RNA into the cell cytoplasm, and (d) determining host and tissue tropism by recognition of cell-specific cell-membrane receptors The virus uses these membrane receptors to enter the target cells [6]. Effective antiviral therapy is not yet clinically available, some promising anti-picornavirus drugs reduce the duration of illness among adults with enteroviral aseptic meningitis [3,4,9,13]. Other “capsid-binding” compounds are pirodavir and its derivatives, which have proved to be effective in intranasal treatment of patients with a common cold caused by some strains of human Rhinoviruses [18]. In this study we tested several novel anti-rhinovirus compounds and demonstrated that some modifications of the central hydrocarbon chain of the molecules could lead to new interesting drugs with an improved activity for certain Rhinovirus strains and a decreased cytotoxicity on cell cultures
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