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

Abstract

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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“…The use of ribavirin is contraindicated in pregnancy; however, its use in HEV-ACLF is worth testing in selected cases. There have been attempts to evaluate alternative drugs in treating difficult patients with HEV-gt3 chronic hepatitis [152]. Inhibits replication in vitro A clinical trial demonstrated that sofosbuvir was not effective on HEV [153] The role is unclear.…”

“…Hepatitis E ORF2 expression, self-assembly, and virus-like particles with native HEV (T = 3) and assembled VLP (T = 1). HEV ORF2 proteins with different lengths have been expressed and purified in several systems in order to determine their particle-forming properties [152]. The native HEV particles have 660 aa with T = 3 icosahedral symmetry and 180 units of the ORF2 protein encircling HEV RNA [100].…”

“…The use of ribavirin is contraindicated in pregnancy; however, its use in HEV-ACLF is worth testing in selected cases. There have been attempts to evaluate alternative drugs in treating difficult patients with HEV-gt3 chronic hepatitis [ 152 ].…”

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“…This substance, however, will require additional validation by in vivo testing in animal models and pharmacokinetic/pharmacodynamic investigations [128]. A recent study [129] showed that the antimalarial Artesunate was able to inhibit HEV replication by directly blocking both the helicase and the RNA-dependent RNA polymerase. A further element of interest about this drug is represented by the fact that it is safe in pregnant women, who are well-known high-risk individuals.…”

“…Non-pregnant patients with chronic HEV infection were shown to benefit from a 12-week course of ribavirin (RBV) monotherapy [ 111 ]. RBV is a guanosine nucleoside analog that acts as a viral polymerase inhibitor, and it has been usually given to solid organ transplant recipients in conjunction with immunosuppressive therapy reduction [ 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 ]. Table 1 contains details about the described drugs and their mechanisms of action in immunocompromised patients.…”