A novel series of indole alkaloid derivatives inhibit dengue and Zika virus infection by interference with the viral replication complex.

Fikatas, Antonios; Vervaeke, Peter; Meyen, Eef; Llor, Nuria; Ordeix, Sergi; Boonen, Ine; Bletsa, Magda; Kafetzopoulou, Liana Eleni; Lemey, Philippe; Amat, Mercedes; Pannecouque, Christophe; Schols, Dominique

Here, we identified a novel class of compounds, which demonstrated good antiviral activity against dengue and Zika virus infection. These derivatives constitute intermediates in the synthesis of indole (ervatamine-silicine) alkaloids and share a tetracyclic structure with an indole and a piperidine fused to a seven-membered carbocyclic ring. Structure-activity relationship studies indicated the importance of substituent at C-6 position and especially the presence of a benzylester for the activity and cytotoxicity of the molecules. In addition, the stereochemistry at C-7 and C-8 positions, as well as the presence of oxazolidine ring influenced the potency of the compounds. Mechanism of action studies with two analogues of this family (compounds 22 and trans-14) showed that this class of molecules can suppress viral infection during the later stages of the replication cycle (RNA replication/assembly). Moreover, a cell-dependent antiviral profile of the compounds against several Zika strains was observed, thus possibly implying the involvement of cellular factor(s) in the activity of the molecules. Sequencing of compounds-resistant Zika mutants revealed a single non-synonymous amino acid mutation (aspartic acid to histidine) at the beginning of the predicted transmembrane domain 1 of NS4B protein, which plays a vital role in the formation of the viral replication complex. To conclude, our study provides detailed information on a new class of NS4B-associated inhibitors and strengthens the importance of identifying host-viral interactions in order to tackle flavivirus infections.