A Novel Series of Indole Alkaloid Derivatives Inhibit Dengue and Zika Virus Infection by Interference with the Viral Replication Complex
| Autor: | Philippe Lemey, Dominique Schols, Peter Vervaeke, Antonios Fikatas, Liana E. Kafetzopoulou, Eef Meyen, Sergi Ordeix, Mercedes Amat, Ine Boonen, Núria Llor, Christophe Pannecouque, Magda Bletsa |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
030106 microbiology Dengue virus Viral Nonstructural Proteins medicine.disease_cause Virus Replication Antiviral Agents Zika virus Indole Alkaloids Dengue 03 medical and health sciences Aspartic acid cross resistance medicine Humans Pharmacology (medical) NS4B protein Pharmacology Indole test dengue virus biology Indole alkaloid Chemistry Zika Virus Infection Zika Virus biology.organism_classification mechanisms of action Transmembrane domain 030104 developmental biology Infectious Diseases SAR studies Viral replication Biochemistry Viral replication complex |
| Zdroj: | Antimicrob Agents Chemother |
| ISSN: | 1098-6596 |
| Popis: | 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. ispartof: ANTIMICROBIAL AGENTS AND CHEMOTHERAPY vol:65 issue:8 ispartof: location:United States status: published |
| Databáze: | OpenAIRE |
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