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

Autor: Tietcheu Galani BR; Laboratory of Applied Biochemistry, Department of Biological Sciences, Faculty of Science, University of Ngaoundere, P.O. Box 454, Ngaoundere, Cameroon.; Laboratory of Pharmacology and Toxicology, Department of Biochemistry, Faculty ofScience, University of Yaounde I, P.O. Box 812, Yaounde, Cameroon., Ayissi Owona VB; Laboratory of Pharmacology and Toxicology, Department of Biochemistry, Faculty ofScience, University of Yaounde I, P.O. Box 812, Yaounde, Cameroon., Guemmogne Temdie RJ; Laboratory of Medicinal Plants, Health, and Galenic Formulation, Department of Biological Sciences, Faculty of Science, University of Ngaoundere, P.O. Box 454, Ngaoundere, Cameroon., Metzger K; University of Lille, CNRS, INSERM, CHU Lille, Pasteur Institute of Lille, U1019-UMR9017-CIIL-Center for Infection and Immunity of Lille, 59000 Lille, France., Atsama Amougou M; Laboratory of Pharmacology and Toxicology, Department of Biochemistry, Faculty ofScience, University of Yaounde I, P.O. Box 812, Yaounde, Cameroon.; Research Center for Emerging and Reemerging Infectious Diseases (CREMER-IMPM), Virology Unit, P.O. Box 906, Yaounde, Cameroon., Djamen Chuisseu PD; Department of Medicine, Medical and Biomedical Sciences, Higher Institute of Health Sciences, Université Des Montagnes, P.O. Box 208, Bangangte, Cameroon., Fondjo Kouam A; Laboratory of Pharmacology and Toxicology, Department of Biochemistry, Faculty ofScience, University of Yaounde I, P.O. Box 812, Yaounde, Cameroon.; Department of Biomedical Sciences, Faculty of Health Sciences, University of Buea, P.O Box 63, Buea, South West Region Cameroon., Ngounoue Djuidje M; Laboratory of Pharmacology and Toxicology, Department of Biochemistry, Faculty ofScience, University of Yaounde I, P.O. Box 812, Yaounde, Cameroon., Aliouat-Denis CM; University of Lille, CNRS, INSERM, CHU Lille, Pasteur Institute of Lille, U1019-UMR9017-CIIL-Center for Infection and Immunity of Lille, 59000 Lille, France., Cocquerel L; University of Lille, CNRS, INSERM, CHU Lille, Pasteur Institute of Lille, U1019-UMR9017-CIIL-Center for Infection and Immunity of Lille, 59000 Lille, France., Fewou Moundipa P; Laboratory of Pharmacology and Toxicology, Department of Biochemistry, Faculty ofScience, University of Yaounde I, P.O. Box 812, Yaounde, Cameroon.
Jazyk: angličtina
Zdroj: In silico pharmacology [In Silico Pharmacol] 2021 May 04; Vol. 9 (1), pp. 35. Date of Electronic Publication: 2021 May 04 (Print Publication: 2021).
DOI: 10.1007/s40203-021-00093-y
Abstrakt: 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.
Competing Interests: Conflict of interestThe authors have no conflict of interest to disclose for this manuscript.
(© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021.)
Databáze: MEDLINE
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