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TARGETING RNA DEPENDENT RNA POLYMERASE: A NEW CLASS OF POTENT COMPOUNDS AGAINST FLAVIVIRUSES. Dr. Eloise Mastrangelo

The genus Flavivirus (Flaviviridae family) consists of over seventy viruses, mostly transmitted by arthropods and pathogenic to humans. Among them, Dengue virus, West Nile virus, Japanese Encephalitis virus, Yellow Fever virus and the recent re-emerging Zika virus, occupy a special area within the RNA virus world. An effective and specific therapy against flaviviruses is currently not available and also the broad-spectrum antiviral ribavirin appears ineffective to treat flavivirus infections.
To date, treatment of flavivirus infections represents an urgent medical need to be addressed. In this regard, a promising strategy is to target the viral polymerase.
RNA dependent RNA polymerases (RdRps) are essential proteins for flavivirus replication. Starting from an in silico docking analysis we identified a new molecule, HeE1-2Tyr, able to inhibit RdRp activity in vitro and effective against a number of flaviviruses in cell culture. Crystal structure of RdRp in complex with the inhibitor, enzyme kinetics, binding studies and protein mutations studies may suggest structure-based optimization of more potent compounds. To date, we synthesized a small library of about 30 chemical variants. Some derivatives showed inhibitory activity in cell cultures against a panel of different flaviviruses with EC50 between 0.01 and 10 μM. The results achieved so far aim to providing innovative information for the design of an entirely new class of antiviral compounds.