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

Galani, Borris Rosnay Tietcheu; Owona, Vincent Brice Ayissi; Temdie, Romeo Joel Guemmogne; Metzger, Karoline; Amougou, Marie Atsama; Chuisseu, Pascal Dieudonne Djamen; Kouam, Arnaud Fondjo; Djuidje, Marceline Ngounoue; Aliouat-Denis, Cécile-Marie; Cocquerel, Laurence; Moundipa, Paul Fewou

doi:10.1007/s40203-021-00093-y

Cited by 11 publications

(6 citation statements)

References 47 publications

(14 reference statements)

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“…To assess whether ART might interact with the HEV helicase and RdRp proteins, which are the key enzymes involved in HEV RNA replication, we used a computational approach. Galani et al [ 38 ] have reported that artemisinin, the parent molecule of ART, has low binding affinity to HEV RdRp; hence, we focused on HEV helicase. As there was no crystal structure of HEV helicase in the PDB database, the 3-D structure was predicted using tomato mosaic virus (ToMV) helicase, which has 32% sequence identity, as a template.…”

Section: Resultsmentioning

confidence: 99%

“…It was documented previously that anti-malarial drugs such as amodiaquine, lumefantrine, and pyrimethamine have potential antiviral activity against HEV-3. As docking of artemisinin, an analog of ART, with different HEV proteins showed low scores with HEV protease and RdRp, it was not investigated further [ 38 ]. Since our experiments showed effective inhibition of HEV-1 with ART, comparable to that observed with ribavirin, we performed a docking simulation with HEV helicase.…”

Section: Discussionmentioning

confidence: 99%

“…Drug repurposing is an attractive strategy that uses a combination of experimental and in silico- based approaches to identify novel pharmacological applications of available drugs [ 37 ]. A recent study by Galani et al [ 38 ] showed that antimalarial drugs such as amodiaquine and lumefantrine are good candidates for use against HEV. The authors used both in silico and in vitro approaches to screen eight licensed antimalarial drugs against HEV.…”

Section: Introductionmentioning

confidence: 99%

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Repurposing of artesunate, an antimalarial drug, as a potential inhibitor of hepatitis E virus

et al. 2023

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Hepatitis E virus (HEV) is endemic in several developing countries of Africa and Asia. It mainly causes self-limiting waterborne infections, in either sporadic or outbreak form. Recently, HEV was shown to cause chronic infections in immunosuppressed individuals. Ribavirin and interferon, the current off-label treatment options for hepatitis E, have several side effects. Hence, there is a need for new drugs. We evaluated the antimalarial drug artesunate (ART) against genotype 1 HEV (HEV-1) and HEV-3 using a virus-replicon-based cell culture system. ART exhibited 59% and 43% inhibition of HEV-1 and HEV-3, respectively, at the highest nontoxic concentration. Computational molecular docking analysis showed that ART can bind to the helicase active site (affinity score, -7.4 kcal/mol), indicating its potential to affect ATP hydrolysis activity. An in vitro ATPase activity assay of the helicase indeed showed 24% and 55% inhibition at 19.5 µM (EC 50 ) and 78 µM concentrations of ART, respectively. Since ATP is a substrate of RNA-dependent RNA polymerase (RdRp) as well, we evaluated the effect of ART on the enzymatic activity of the viral polymerase. Interestingly, ART showed 26% and 40% inhibition of the RdRp polymerase activity at 19.5 µM and 78 µM concentrations of ART, respectively. It could be concluded from these findings that ART inhibited replication of both HEV-1 and HEV-3 by directly targeting the activities of the viral enzymes helicase and RdRp. Considering that ART is known to be safe in pregnant women, we think this antimalarial drug deserves further evaluation in animal models. Supplementary Information The online version contains supplementary material available at 10.1007/s00705-023-05770-1.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Repurposing of artesunate, an antimalarial drug, as a potential inhibitor of hepatitis E virus

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“…The active site residues (i.e., Arg366, Arg399, Gln420, Gln421, Asp444, and Gln446) were selected on the basis of previously reported studies [ 22 ]. A total 100 antimicrobial tetrapeptides were docked to the receptor protein (capsid protein) of HEV.…”

Section: Resultsmentioning

confidence: 99%

“…In another study, Galani et al [ 22 ] investigated eight licensed antimalarial drugs and two anti-hepatitis C virus agents (i.e., sofosbuvir and ribavirin) as inhibitors of five different target proteins of the HEV genome. These ten compounds were docked counter to RdRp, zinc-binding non-structural protein, capsid protein, cryoEM structure of HEV VLP, and the E2s domain of HEV genome.…”

Section: Discussionmentioning

confidence: 99%

Identification of Plant Peptides as Novel Inhibitors of Orthohepevirus A (HEV) Capsid Protein by Virtual Screening

et al. 2023

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Hepatitis E virus (HEV) is the notable causative agent of acute and chronic hepatic, renal, pancreatic, neurological, and hematopoietic blood cell infections with high risk in immunocompromised patients. Hepatic failure is mostly documented among adults, pregnant women, and patients with preexisting liver disease. HEV is a positive sense RNA virus of 7.2 kb genome size with typically three open reading frames (ORFs) which play essential roles in viral replication, genome assembly, and transcription. The mutational substitution in the viral RNA genome makes more it difficult to understand the actual relationship in the host–virus association. ORFs of HEV encode different structural and non-structural proteins and one of them is the capsid protein which is coded by ORF2. The capsid protein mediates the encapsulation of the viral genome as well as being involved in virion assembly. In the current study, the ligand-based docking approach was employed to inhibit the active amino acids of the viral capsid protein. Depending upon S-score, ADMET profiling, and drug scanning, the top ten tetrapeptides were selected as potential drug candidates with no toxicity counter to HEV receptor protein. The S-score or docking score is a mathematical function which predicts the binding affinities of docked complexes. The binding affinity of the predicted drug–target complexes helps in the selectivity of the desired compound as a potential drug. The best two selected peptides (i.e., TDGH with S-score of −8.5 and EGDE with S-score of −8.0) interacted with the active site amino acids of the capsid protein (i.e., Arg399, Gln420, and Asp444). The molecular dynamics simulations of RMSD trajectories of TDGH–capsid protein and EDGE–capsid protein have revealed that both docked complexes were structurally stable. The study revealed that these tetrapeptides would serve as strong potential inhibitors and a starting point for the development of new drug molecules against the HEV capsid protein. In future, in vivo studies are needed to explore selected peptides as potential drug candidates.

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Puzzles for Hepatitis E Virus

Wang,

Zhuang

2023

Advances in Experimental Medicine and Biology

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

Cited by 11 publications

References 47 publications

Repurposing of artesunate, an antimalarial drug, as a potential inhibitor of hepatitis E virus

Repurposing of artesunate, an antimalarial drug, as a potential inhibitor of hepatitis E virus

Identification of Plant Peptides as Novel Inhibitors of Orthohepevirus A (HEV) Capsid Protein by Virtual Screening

Puzzles for Hepatitis E Virus

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