Discovery of berberine, abamectin and ivermectin as antivirals against chikungunya and other alphaviruses

Varghese, Finny S.; Kaukinen, Pasi; Gläsker, Sabine; Bespalov, Maxim M.; Hanski, Leena; Wennerberg, Krister; Kümmerer, Beate M.; Ahola, Tero

doi:10.1016/j.antiviral.2015.12.012

Cited by 170 publications

(171 citation statements)

References 35 publications

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“…[21][22][23] Very recently, antiviral activities of avermectins against chikungunya and other alphaviruses were reported. 24 Our new findings suggest that avermectins also possess anti-PoSaV activity. Additional studies of avermectins are necessary to clarify their unknown antiviral mechanism.…”

Section: Discovery Of Anti-calicivirus Compoundsmentioning

confidence: 67%

Antiviral effect of theaflavins against caliciviruses

et al. 2016

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Caliciviruses are contagious pathogens of humans and various animals. They are the most common cause of viral gastroenteritis in humans, and can cause lethal diseases in domestic animals such as cats, rabbits and immunocompromised mice. In this study, we conducted cytopathic effect-based screening of 2080 selected compounds from our in-house library to find antiviral compounds against three culturable caliciviruses: feline calicivirus, murine norovirus (MNV) and porcine sapovirus (PoSaV). We identified active six compounds, of which two compounds, both related to theaflavins, showed broad antiviral activities against all three caliciviruses; three compounds (abamectin, a mixture of avermectin B1a and B1b; avermectin B1a; and (− )-epigallocatechin gallate hydrate) were effective against PoSaV only; and a heterocyclic carboxamide derivative (BFTC) specifically inhibited MNV infectivity in cell cultures. Further studies of the antiviral mechanism and structure-activity relationship of theaflavins suggested the following: (1) theaflavins worked before the viral entry step; (2) the effect of theaflavins was time-and concentration-dependent; and (3) the hydroxyl groups of the benzocycloheptenone ring were probably important for the anti-calicivirus activity of theaflavins. Theaflavins could be used for the calicivirus research, and as potential disinfectants and antiviral reagents to prevent and control calicivirus infections in animals and humans.

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Section: Discovery Of Anti-calicivirus Compoundsmentioning

confidence: 67%

Antiviral effect of theaflavins against caliciviruses

et al. 2016

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“…Cells in 6-well plates were lysed with 100 l of 2ϫ Laemmli buffer per well and solubilized and blotted as described earlier (21). Primary staining, using antibodies against CHIKV nsP1, nsP3, and capsid (all in-house), E2 proteins (a kind gift from Philippe Desprès, Insitut Pasteur), and mouse anti-actin (Sigma), and secondary staining were done as described earlier (21). Western blot evaluation of signaling was performed as described previously (7).…”

Section: Methodsmentioning

confidence: 99%

“…Using a CHIKV replicon cell line in a high-throughput screen of approximately 3,000 compounds, we recently identified berberine, a relatively nontoxic isoquinoline alkaloid, as a potent inhibitor of CHIKV replication, with an additional effect on virus yield (21). Here, we sought to understand the mode of action of this compound and also addressed the question of its in vivo efficacy.…”

mentioning

confidence: 99%

The Antiviral Alkaloid Berberine Reduces Chikungunya Virus-Induced Mitogen-Activated Protein Kinase Signaling

Varghese

Thaa

Amrun

et al. 2016

J Virol

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Chikungunya virus (CHIKV) has infected millions of people in the tropical and subtropical regions since its reemergence in the last decade. We recently identified the nontoxic plant alkaloid berberine as an antiviral substance against CHIKV in a highthroughput screen. Here, we show that berberine is effective in multiple cell types against a variety of CHIKV strains, also at a high multiplicity of infection, consolidating the potential of berberine as an antiviral drug. We excluded any effect of this compound on virus entry or on the activity of the viral replicase. A human phosphokinase array revealed that CHIKV infection specifically activated the major mitogen-activated protein kinase (MAPK) signaling pathways extracellular signal-related kinase (ERK), p38 and c-Jun NH 2 -terminal kinase (JNK). Upon treatment with berberine, this virus-induced MAPK activation was markedly reduced. Subsequent analyses with specific inhibitors of these kinases indicated that the ERK and JNK signaling cascades are important for the generation of progeny virions. In contrast to specific MAPK inhibitors, berberine lowered virus-induced activation of all major MAPK pathways and resulted in a stronger reduction in viral titers. Further, we assessed the in vivo efficacy of berberine in a mouse model and measured a significant reduction of CHIKV-induced inflammatory disease. In summary, we demonstrate the efficacy of berberine as a drug against CHIKV and highlight the importance of the MAPK signaling pathways in the alphavirus infectious cycle. IMPORTANCEChikungunya virus (CHIKV) is a mosquito-borne virus that causes severe and persistent muscle and joint pain and has recently spread to the Americas. No licensed drug exists to counter this virus. In this study, we report that the alkaloid berberine is antiviral against different CHIKV strains and in multiple human cell lines. We demonstrate that berberine collectively reduced the virus-induced activation of cellular mitogen-activated protein kinase signaling. The relevance of these signaling cascades in the viral life cycle was emphasized by specific inhibitors of these kinase pathways, which decreased the production of progeny virions. Berberine significantly reduced CHIKV-induced inflammatory disease in a mouse model, demonstrating efficacy of the drug in vivo. Overall, this work makes a strong case for pursuing berberine as a potential anti-CHIKV therapeutic compound and for exploring the MAPK signaling pathways as antiviral targets against alphavirus infections. C hikungunya virus (CHIKV) is the causative agent of chikungunya fever, a disease spread by Aedes mosquitoes and characterized by a sudden onset of febrile illness, nausea, headache, and most importantly, severe and persistent musculoskeletal pain (1). It reemerged in tropical Asia and Africa 1 decade ago and since 2013 has infected more than 1.5 million people in the Americas (2). So far, no licensed vaccine or antiviral treatment exists to counter this disease. Over the years, many research groups have focused on...

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“…Полу-чали 3.3 г продукта (58 %). (1H, м, 2-СH), 3.41 (3H, c, 3"-OCH 3 ), 3.46 (3H, c, 3'-OCH 3 ), 3.49-3.95 (7H, м, 5"-СH, 5'-СH, 3"-СH, 3'-СH, 25-СН (8). К раствору 0.14 г (0.27 ммоль) соединения (6) …”

Section: экспериментальная частьunclassified

“…[7] Ивермектин В1 отличается низкой токсичностью для теплокровных, высокой стабильностью, интенсив-ностью противопаразитарной активности и широким спектром действия, включая противовирусную актив-ность. [8][9][10][11][12] В данной работе осуществлен синтез новых про-изводных ивермектина 1b на основе углеводов и амино-кислот, которые расширяют диапазон имеющихся пре-паратов и позволяют повысить их водорастворимость, что значительно облегчает проведение биохимических исследований по определению биологической актив-ности соединений. Пропаргиловый эфир L-гистидина (4).…”

Section: Introductionunclassified