Abstract
Taking berberine (BBR) as the lead, 23 new BBR derivatives were synthesized and examined for their antiviral activities against four different genotype enterovirus 71 (EV71) strains with a cytopathic effect (CPE) assay. Structure-activity relationship (SAR) studies indicated that introduction of a suitable substituent at the 9-position might be beneficial for potency. Among them, compound 2d exhibited most potent activities with IC50 values of 7.12–14.8 μM, similar to that of BBR. The effect of 2d was further confirmed in a dose-dependent manner both in RNA and protein level. The mechanism revealed that 2d could inhibit the activation of MEK/ERK signaling pathway. Meanwhile, it could suppress the EV71-induced autophagy by activating AKT and inhibiting the phosphorylation of JNK and PI3KIII proteins. We consider BBR derivatives to be a new family of anti-EV71 agents through targeting host components, with an advantage of broad-spectrum anti-EV71 potency.
Highlights
Enterovirus 71 (EV71), a single-stranded positive-sense RNA virus belonging to the enterovirus genus of the Picornaviridae family, is the primary cause of the hand, foot and mouth disease (HFMD), which is widely spread among infants and young children, especially those under 5 years old [1,2].enterovirus 71 (EV71) was first isolated from patients with central nervous system (CNS) diseases in California in 1969 and HFMD caused by EV71 infections usually is self-limiting, but some EV71-caused HFMD cases have been associated with neurological diseases such as aseptic meningitis, myocarditis and pulmonary edema [3,4,5]
Discussion we described the synthesis of 23 new BBR derivatives, structure-activity relationship (SAR) analysis and primary mechanism of action of action of the representative compound
A total of Discussion twenty-three new BBR derivatives were semi-synthesized as displayed in Schemes
Summary
Enterovirus 71 (EV71), a single-stranded positive-sense RNA virus belonging to the enterovirus genus of the Picornaviridae family, is the primary cause of the hand, foot and mouth disease (HFMD), which is widely spread among infants and young children, especially those under 5 years old [1,2].EV71 was first isolated from patients with central nervous system (CNS) diseases in California in 1969 and HFMD caused by EV71 infections usually is self-limiting, but some EV71-caused HFMD cases have been associated with neurological diseases such as aseptic meningitis, myocarditis and pulmonary edema [3,4,5]. Up to now there is still no effective drug for the prevention and treatment of HFMD in the clinic. This situation has resulted in a very pressing need for the discovery of novel anti-EV71 drug candidates for the control of infectious diseases arising from EV71 [6,7]. We have been working to find innovative drug candidates from Chinese natural products such as berberine (BBR, Figure 1), which has been widely used in China for decades against diarrhea as a Traditional Chinese Medicine (TCM). We have continuously reported that BBR derivatives possess various pharmacological effects, such as antibacterial [8], anti-Coxsackie virus [9], Molecules 2018, 23, 2084; doi:10.3390/molecules23082084 www.mdpi.com/journal/molecules
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