1,5-Dicaffeoylquinic Acid Blocks EBOV Replication Counteracting the IFN-beta Production Inhibition by the VP35 Ebola Virus Protein

Ebola virus (EBOV) is one of the deadliest infective agents whose high lethality is linked to the ability to efficiently bypass the host’s innate antiviral response. EBOV multifunctional protein VP35 plays a major role in viral replication both as polymerase cofactor and masking agent. VP35, in fact, hides the non-self 5’-ppp dsRNA from the cellular receptor RIG-I, preventing its activation and inhibiting the IFN-b production. Blocking VP35-dsRNA interaction and IFN-b suppression is a validated strategy to overcome EBOV infection. We have previously established a robust fluorescence-based biochemical assay to measure VP35-dsRNA interaction and a miniaturized gene reporter cell-based assay to measure the VP35 inhibition of the IFN-b production. Hence, we screened a library of natural extracts and found that 1,5-dicaffeoylquinic acid (DCA) inhibits dsRNA-VP35 binding with an IC50 value of 8.5 μM, it reverts the EBOV VP35 inhibition of interferon production, while it does not induce IFN production by itself. Furthermore, DCA was then tested in an EBOV minigenome replication, showing no inhibition of the VP35 polymerase cofactor activity. While, when DCA was tested on the replication of an EBOV isolate derived from the 2014 West Africa outbreak in IFN-susceptible A459 cells, it was able to inhibit viral replication with an EC50 value of 9.1 μM, showing no significant cytotoxicity. Overall, our data indicate that DCA is a powerful inhibitor of EBOV replication targeting VP35 and subverting the viral inhibitory effect on IFN production.