In silico and in vitro screening of licensed antimalarial drugs for repurposing as inhibitors of hepatitis E virus.

ABSTRACT: Hepatitis E virus (HEV) infection is emerging in Cameroon and represents one of the most common causes of acute hepatitis and jaundice. Moreover, earlier reports showed evidence of falciparum malaria/HEVcoexistence. Although the Sofosbuvir/Ribavirin combination was recently proposed in the treatment of HEV-infected patients, no specific antiviral drug has been approved so far, thereby urging the search for new therapies. Fortunately, drug repurposing offers a good alternative to this end. In this study, we report the in silico and in vitro activities of 8 licensed antimalarial drugs and two anti-hepatitis C virus agents used as references (Sofosbuvir, and Ribavirin), for repurposing as antiviral inhibitors against HEV. Compounds were docked against five HEV-specific targets including the Zinc-binding non-structural protein (6NU9), RNA-dependent RNA polymerase (RdRp), cryoEM structure of HEV VLP, genotype 1 (6LAT), capsid protein ORF-2, genotype 3 (2ZTN), and the E2s domain of genotype 1 (3GGQ) using the iGEMDOCK software and their pharmacokinetic profiles and toxicities were predicted using ADMETlab2.0. Their in vitro effects were also assessed on a gt 3 p6Gluc replicon system using the luciferase reporter assay. The docking results showed that Sofosbuvir had the best binding affinities with 6NU9 (- 98.22 kcal/mol), RdRp (- 113.86 kcal/mol), 2ZTN (- 106.96 kcal/mol), while Ribavirin better collided with 6LAT (- 99.33 kcal/mol). Interestingly, Lumefantrine showed the best affinity with 3GGQ (-106.05 kcal/mol). N-desethylamodiaquine and Amodiaquine presented higher binding scores with 6NU9 (- 93.5 and - 89.9 kcal/mol respectively vs - 80.83 kcal/mol), while Lumefantrine had the greatest energies with RdRp (- 102 vs - 84.58), and Pyrimethamine and N-desethylamodiaquine had stronger affinities with 2ZTN compared to Ribavirin (- 105.17 and - 102.65 kcal/mol vs - 96.04 kcal/mol). The biological screening demonstrated a significant (P < 0.001) antiviral effect on replication with 1 µM N-desethylamodiaquine, the major metabolite of Amodiaquine. However, Lumefantrine showed no effect at the tested concentrations (1, 5, and 10 µM). The biocomputational analysis of the pharmacokinetic profile of both drugs revealed a low permeability of Lumefantrine and a specific inactivation by CYP3A2 which might partly contribute to the short half-time of this drug. In conclusion, Amodiaquine and Lumefantrine may be good antimalarial drug candidates for repurposing against HEV. Further in vitro and in vivo experiments are necessary to validate these predictions. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-021-00093-y.

Natural limonoids protect mice from alcohol-induced liver injury.

Background Alcoholic liver disease (ALD) is regarded as a global health problem with limited therapeutic options. Previous studies highlighted some anticancer, antiviral, and hepatoprotective activities of limonoids, but the effects of these compounds on ALD remain unknown. The present study aimed to evaluate the effect of some natural limonoids on ethanol-induced liver injury. Methods Thirty-five albino mice (Mus musculus) were administered with 40% ethanol in the presence or absence of the different limonoids [including three havanensin-type limonoids, TS1, TS3, Rubescin D isolated from an African medicinal plant, Trichilia rubescens Oliv. (Meliaceae), and one limonin], or silymarin at 50 mg/kg for 3 days. Thereafter, the effect of the most active compound was evaluated in a chronic model of ALD. For this purpose, 24 mice with each group consisting of six mice were administered orally with 40% ethanol and limonoid at different doses (50, 75, and 100 mg/kg) for 28 days. Finally, biochemical parameters such as alanine aminotransferase (ALT), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), triglyceride (TG), and tumor necrosis factor α (TNF-α) levels were quantified in liver homogenates. Results All tested limonoids significantly (p < 0.01) reduced ALT levels relative to the negative control in the acute model. However, in comparison to other limonoids, limonin at 50 and 75 mg/kg significantly reduced TG, MDA, and TNF-α levels (1.8-fold); alleviated leukocyte infiltration in liver tissue; significantly increased the activity of SOD; and decreased those of CAT better than silymarin used as a positive control at 50 mg/kg. Conclusions These data suggest that limonin possesses protective effects on long-term alcohol poisoning partially due to antioxidant and anti-inflammatory mechanisms.

A new device for real-time peroperative monitoring of ossicular chain reconstruction during middle ear surgery.

To limit functional surgical failure and reduce the rate of revision surgery in case of surgical ossicular chain reconstruction, a piezoelectric device was developed for assessment of ossicular chain vibrations during the middle ear surgery. The device resembled a pen and consisted of a reusable main body and a disposable sensitive head including piezoelectric polymer sensor. Almost all of components of the device were made of polymer for light weight and for acoustic impedance matching to the middle ear system. Several frequencies can be analyzed simultaneously and several measures can be taken by time. The results showed that the device can record normal and reconstructed ossicular chain vibration in response to an acoustic stimulation, with similar results to those achieved by laser Doppler vibrometer. This light, handheld and low-cost device allows fast, easy and safe assessments of normal ossicular chain mobility and ossicular chain reconstruction efficiency. Primary pre-clinical trial showed very promising performance of the device that could be used to qualitatively control ossiculoplasty during real-time surgical procedure. Clinical assessments will be done to further evaluate the real-life performance of the device.

Preparation and characterization of P(VDF-TrFE)/Al2O3 nanocomposite.

Hybrid nanocomposites based on crystalline nanoparticles dispersed in polymer matrix have been widely studied in the past few years because of the ability of these materials to combine the properties of organic polymer and inorganic nanoparticles. The aim of this work is to tune the mechanical properties of a piezoelectric polymer by adding nanoparticles to the matrix. In this paper, alumina nanoparticles were dispersed in the copolymer P(VDF-TrFE), which exhibits high piezoelectric coefficient after polarization under high electric field without needing stretching during the polarization process. Transmission electron microscopy and scanning electron microscopy demonstrate the high rate of welldispersed nanoparticles with 10% of alumina nanoparticles added to the matrix. Piezoelectric measurements indicate that P(VDF-TrFE) may be filled by up to 10 wt% of alumina while retaining its high piezoelectric properties and increasing its elastic constant by more than 20%, measured by Brillouin spectroscopy. This work opens a wide range of applications using nanoparticles with nonlinear optical, pyroelectric, magnetic, or ferroelectric properties.

Effect of ultrasonication and dispersion stability on the cluster size of alumina nanoscale particles in aqueous solutions.

This study deals with the deagglomeration of nanoparticles in low concentration suspensions in water, protic polar solvent for polymers such as poly(vinyl alcohol) (PVA). The influence of the main parameters of ultrasonication such as time, power and irradiation modes (continuous, pulsed) on the cluster size of aluminium oxide nanoparticles 1 mg/ml in aqueous solutions was investigated. Power-law dependence of size reduction on ultrasonic time was observed. The study indicated an optimum power input, i.e. at higher vibration amplitude the break up of nanoparticle clusters was no better and there was a risk of reagglomeration occurring during a long ultrasonication. Under optimal conditions, continuous and pulsed irradiations showed almost the same efficiency of deagglomeration over a given time. This result provides alternative operating conditions for attaining the smallest size of the alumina aggregates in suspension. The influence of stabilization on the cluster size was also studied. Alumina nanoparticles were stabilized by electrostatic forces against reagglomeration without the need for dispersants, and the enhancement of dispersion stability using electrostatic, steric effects had no significant effect on the aggregate size. On the contrary, the adsorption of high molecular weight polyelectrolytes onto the particle surface could lead to reagglomeration due to material bridges between particle surfaces and even flocculation.