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In Central Eurasia, the availability of drugs that are inhibitors of the SARS-CoV-2 virus and have proven clinical efficacy is still limited. The aim of this study was to evaluate the activity of drugs that were available in Kazakhstan during the acute phase of the epidemic against SARS-CoV-2. Antiviral activity is reported for Favipiravir, Tilorone, and Cridanimod, which are registered drugs used for the treatment of respiratory viral infections in Kazakhstan. A licorice (Glycyrrhiza glabra) extract was also incorporated into this study because it offered an opportunity to develop plant-derived antivirals. The Favipiravir drug, which had been advertised in local markets as an anti-COVID cure, showed no activity against SARS-CoV-2 in cell cultures. On the contrary, Cridanimod showed impressive high activity (median inhibitory concentration 66 μg/mL) against SARS-CoV-2, justifying further studies of Cridanimod in clinical trials. Tilorone, despite being in the same pharmacological group as Cridanimod, stimulated SARS-CoV-2 replication in cultures. The licorice extract inhibited SARS-CoV-2 replication in cultures, with a high median effective concentration of 16.86 mg/mL. Conclusions: The synthetic, low-molecular-weight compound Cridanimod suppresses SARS-CoV-2 replication at notably low concentrations, and this drug is not toxic to cells at therapeutic concentrations. In contrast to its role as an inducer of interferons, Cridanimod is active in cells that have a genetic defect in interferon production, suggesting a different mechanism of action. Cridanimod is an attractive drug for inclusion in clinical trials against SARS-CoV-2 and, presumably, other coronaviruses. The extract from licorice shows low activity against SARS-CoV-2. At the same time, high doses of 2 g/kg of this plant extract show little or no acute toxicity in animal studies; for this reason, licorice products can still be considered for further development as a safe, orally administered adjunctive therapy. Full article

The synthetic compounds, Tilorone and Cridanimod, have the antiviral activity which initially had been ascribed to the capacity to induce interferon. Both drugs induce interferon in mice but not in humans. This study investigates whether these compounds have the antiviral activity in mice and rats since rats more closely resemble the human response. Viral-infection models were created in CD-1 mice and Wistar rats. Three strains of Venezuelan equine encephalitis virus were tested for the performance in these models. One virus strain is the molecularly cloned attenuated vaccine. The second strain has major virulence determinants converted to the wild-type state which are present in virulent strains. The third virus has wild-type virulence determinants, and in addition, is engineered to express green fluorescent protein. Experimentally infected animals received Tilorone or Cridanimod, and their treatment was equivalent to the pharmacopoeia-recomended human treatment regimen. Tilorone and Cridanimod show the antiviral activity in mice and rats and protect the mice from death. In rats, both drugs diminish the viremia. These drugs do not induce interferon-alpha or interferon-beta in rats. The presented observations allow postulating the existence of an interferon-independent and species-independent mechanism of action. Full article