TY - JOUR
T1 - Discovery of berberine, abamectin and ivermectin as antivirals against chikungunya and other alphaviruses
AU - Varghese, Finny S
AU - Kaukinen, Pasi
AU - Gläsker, Sabine
AU - Bespalov, Maxim
AU - Hanski, Leena
AU - Wennerberg, Krister
AU - Kümmerer, Beate M
AU - Ahola, Tero
N1 - Copyright © 2016 Elsevier B.V. All rights reserved.
PY - 2016/2/1
Y1 - 2016/2/1
N2 - Chikungunya virus (CHIKV) is an arthritogenic arbovirus of the Alphavirus genus, which has infected millions of people after its re-emergence in the last decade. In this study, a BHK cell line containing a stable CHIKV replicon with a luciferase reporter was used in a high-throughput platform to screen approximately 3000 compounds. Following initial validation, 25 compounds were chosen as primary hits for secondary validation with wild type and reporter CHIKV infection, which identified three promising compounds. Abamectin (EC50 = 1.5 μM) and ivermectin (EC50 = 0.6 μM) are fermentation products generated by a soil dwelling actinomycete, Streptomyces avermitilis, whereas berberine (EC50 = 1.8 μM) is a plant-derived isoquinoline alkaloid. They inhibited CHIKV replication in a dose-dependent manner and had broad antiviral activity against other alphaviruses--Semliki Forest virus and Sindbis virus. Abamectin and ivermectin were also active against yellow fever virus, a flavivirus. These compounds caused reduced synthesis of CHIKV genomic and antigenomic viral RNA as well as downregulation of viral protein expression. Time of addition experiments also suggested that they act on the replication phase of the viral infectious cycle.
AB - Chikungunya virus (CHIKV) is an arthritogenic arbovirus of the Alphavirus genus, which has infected millions of people after its re-emergence in the last decade. In this study, a BHK cell line containing a stable CHIKV replicon with a luciferase reporter was used in a high-throughput platform to screen approximately 3000 compounds. Following initial validation, 25 compounds were chosen as primary hits for secondary validation with wild type and reporter CHIKV infection, which identified three promising compounds. Abamectin (EC50 = 1.5 μM) and ivermectin (EC50 = 0.6 μM) are fermentation products generated by a soil dwelling actinomycete, Streptomyces avermitilis, whereas berberine (EC50 = 1.8 μM) is a plant-derived isoquinoline alkaloid. They inhibited CHIKV replication in a dose-dependent manner and had broad antiviral activity against other alphaviruses--Semliki Forest virus and Sindbis virus. Abamectin and ivermectin were also active against yellow fever virus, a flavivirus. These compounds caused reduced synthesis of CHIKV genomic and antigenomic viral RNA as well as downregulation of viral protein expression. Time of addition experiments also suggested that they act on the replication phase of the viral infectious cycle.
KW - Alphavirus/drug effects
KW - Animals
KW - Antiviral Agents/pharmacology
KW - Berberine/pharmacology
KW - Cell Line
KW - Cell Line, Tumor
KW - Chikungunya Fever/drug therapy
KW - Chikungunya virus/drug effects
KW - Cricetinae
KW - DNA, Viral/antagonists & inhibitors
KW - Flavivirus/drug effects
KW - Humans
KW - Ivermectin/analogs & derivatives
KW - RNA, Viral/antagonists & inhibitors
KW - Replicon/drug effects
KW - Viral Proteins/antagonists & inhibitors
KW - Virus Replication/drug effects
KW - Yellow fever virus/drug effects
U2 - 10.1016/j.antiviral.2015.12.012
DO - 10.1016/j.antiviral.2015.12.012
M3 - Journal article
C2 - 26752081
SN - 0166-3542
VL - 126
SP - 117
EP - 124
JO - Antiviral Research
JF - Antiviral Research
ER -