A Novel Series of Indole Alkaloid Derivatives Inhibit Dengue and Zika Virus Infection by Interference with the Viral Replication Complex

Antimicrob Agents Chemother. 2021 Jul 16;65(8):e0234920. doi: 10.1128/AAC.02349-20. Epub 2021 Jul 16.

Abstract

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 position C-6 and especially the presence of a benzyl ester for the activity and cytotoxicity of the molecules. In addition, the stereochemistry at C-7 and C-8, as well as the presence of an 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, possibly implying the involvement of a cellular factor(s) in the activity of the molecules. Sequencing of compound-resistant Zika mutants revealed a single nonsynonymous 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-virus interactions in order to tackle flavivirus infections.

Keywords: NS4B protein; SAR studies; Zika virus; cross resistance; dengue virus; indole alkaloids; mechanisms of action.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dengue*
  • Humans
  • Indole Alkaloids
  • Viral Nonstructural Proteins
  • Virus Replication
  • Zika Virus Infection* / drug therapy
  • Zika Virus*

Substances

  • Indole Alkaloids
  • Viral Nonstructural Proteins