Amaryllidaceae Alkaloid Cherylline Inhibits the Replication of Dengue and Zika Viruses

Abstract

Dengue fever, caused by dengue virus (DENV) is the most prevalent arthropod-borne viral disease, and is endemic in many tropical and sub-tropical parts of the world with an increasing incidence in temperate regions. The closely related flavivirus Zika virus (ZIKV) can be transmitted vertically in utero and causes congenital Zika syndrome and other birth defects. In adults, ZIKV is associated with Guillain-Barré syndrome. There are no approved antiviral therapies against neither viruses. Effective antiviral compounds are urgently needed. Amaryllidaceae alkaloids (AAs) are a specific class of nitrogen-containing compounds produced by plants of the Amaryllidaceae family with numerous biological activities. Recently, the AA lycorine was shown to present strong antiflaviviral properties. Previously, we demonstrated that Crinum jagus contained lycorine and several alkaloids of cherylline, crinine and galanthamine-types with unknown antiviral potential. In this study, we explored their biological activities. We show that C. jagus crude alkaloid extract inhibited DENV infection. Among the purified AAs, cherylline inhibited efficiently both DENV (EC 50 =8.8 μM) and ZIKV replication (EC 50 =20.3 μM), but had no effect on HIV-1 infection. Time-of-drug-addition and -removal experiments identified a post-entry step as the one targeted by cherylline. Consistently, using subgenomic replicons and replication-defective genomes, we demonstrate that cherylline specifically hinders the viral RNA-synthesis step but not viral translation. In conclusion, AAs are an underestimated source of antiflavivirus compounds, including the effective inhibitor cherylline that could be optimized for new therapeutic approaches.

Isolation and Biological Characterization of Homoisoflavanoids and the Alkylamide N-p-Coumaroyltyramine from Crinum biflorum Rottb., an Amaryllidaceae Species Collected in Senegal

“…rigidifolia. The previously undescribed homoisoflavanoinds were also fully characterized by spectroscopic data (UV, IR, 1 H and 13 C NMR and EIMS) but any experiments to determine the absolute configuration of the chiral compounds were neither carried out nor discussed. Among the homoisoflavanoids isolated as new compounds, only for some of them, including 12 (=1), was reported the optical specific activity.…”

“…Electronic circular dichroism (ECD) spectra were recorded on a JASCO J-815 spectrometer (Jasco, Tokyo, Japan) in CH 3 OH. 400 Anova Advance (Bruker, Karlsruhe, Germany) and Inova 500 MHz (Varian, Palo Alto, CA, USA) instruments were used to record 1 H and 13 C NMR spectra in CDCl 3 or CD 3 OD at 400/100 or 500/125 MHz, respectively. The same solvents were used as internal standards.…”

“…The anti-HIV-1 activity of compounds 1-5 was evaluated using VSV-G pseudotyped NL43 GFP infection of human monocytic THP-1 cells. THP-1 and NL4-3 GFP were generously provided by Lionel Berthoux and Amita Singh and are described in Ka et al (2021) [13]. THP-1 cells were seeded at 2.0 × 10 4 cells per well in 96 well-plates.…”

“…The purification of the crude organic extract from bulbs of C. biflorum allowed us to isolate four homoisoflavanoids (( 1)-( 4), Figure 1) identified using spectroscopic (essentially 1D and 2D 1 H and 13 C NMR and HR MS) methods as 5,6,7-trimethoxy-3-(4hydroxybenzyl)chroman-4-one (1), as 3-hydroxy-5,6,7-trimethoxy-3-(4-hydroxybenzyl)chroman-4-one (2), as 3-hydroxy-5,6,7-trimethoxy-3-(4-methoxybenzyl)chroman-4-one (3) and as 5,6,7-trimethoxy-3-(4-methoxybenzyl)chroman-4-one (4). The identification of 1 was performed comparing its 1 H NMR spectrum with that reported in the literature when it was isolated for the first time from Scilla nervosa, subsp.…”

“…Three undescribed alkaloids, gigantelline, gigantellinine and gigancrinine with anti-acetylcholinesterase activity, were recently isolated from Crinum jagus , together with the already known lycorine-, cherylline-, galanthamine- and crinine-type alkaloids [ 12 ]. We also showed that C. jagus crude alkaloid extract inhibited Dengue virus (DENV) infection [ 13 ]. Among the alkaloids isolated from this plant, cherylline inhibited efficiently of both DENV (EC 50 = 8.8 μM) and Zika virus (ZIKV) replication (EC 50 = 20.3 μM), whereas it was ineffective on human immunodeficiency virus type 1 (HIV-1) infection.…”