Antiviral Effects of Artemisinin and Its Derivatives

Artemisinin, a sesquiterpene lactone compound with a peroxide bridge structure, is extracted and isolated from the medicinal plant Artemisia annua L. Over the years, extensive research has revealed a broad spectrum of potential applications for artemisinin and its derivatives, including antitumor, immune regulation, osteoporosis prevention, antibacterial, and antiviral roles. This article provides an in-depth review of the antiviral activities of artemisinin and its derivatives against diverse viruses, such as Coronaviridae, Herpesviridae, and Flaviviridae. The findings suggest that artemisinin-type compounds could offer new strategies to combat emerging viral diseases for which no effective antiviral drugs are currently available.

Coronaviridae

Coronaviruses (CoVs) belong to the family Coronaviridae, order Nidovirales, and genus Coronavirus. They are enveloped viruses with positive-sense, single-stranded RNA genomes ranging from 26 kb to 32 kb in size. Like hydroxychloroquine (HCQ), artemisinin-based compounds can prevent the docking process of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor-binding domain to the human receptor angiotensin-converting enzyme 2 (ACE2). This is achieved by selectively interacting with the Lys353 and Lys31 binding hotspots via hydrogen bond formation. Notably, artemisinin and its derivatives produced better Vina docking scores (-7.1 kcal/mol for artelinic acid vs. -5.5 kcal/mol for HCQ) and much lower inhibition constants (Ki) than HCQ.

In a clinical trial involving 41 SARS-CoV-2-positive patients, the combination of artemisinin and piperaquine (ART-PQP) demonstrated therapeutic efficacy. The administration of ART-PQP reduced viral titers to undetectable levels by day 21, whereas patients in the control group cleared the virus by day 36. However, the study did not rule out the interference of other antivirals, as many patients also received multiple other treatments, including interferon (IFN)-α-1b, ribavirin, oseltamivir, lopinavir, and carrimycin.

Herpesviridae

The family Herpesviridae includes well-known human herpesviruses such as Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), herpes zoster virus, and herpes simplex virus types 1 and 2. The antiviral capabilities of artemisinin and its derivatives have been extensively studied in this family.

Epstein-Barr Virus (EBV)

EBV, a human γ-herpesvirus, is one of the most common herpesviruses. The half-maximal inhibitory concentration (IC50) of artesunate against EBV strain B95-8 in vitro was 6.4 ± 2.7 µmol/L in Raji cells (immortalized B lymphocytes) and 3.1 ± 0.9 µmol/L in 293T cells (immortalized epithelial cells). Importantly, artesunate did not exhibit significant cytotoxic effects on Raji cells at concentrations ranging from 0.1 µmol/L to 90 µmol/L. The antiviral mechanism of artesunate involves preventing the synthesis of viral immediate-early proteins rather than inhibiting EBV cell adsorption or entry. This makes artesunate superior to many conventional therapeutic agents in inhibiting ongoing lytic replication.

Human Cytomegalovirus (HCMV)

HCMV is the most prevalent virus in the Herpesviridae family, affecting a large portion of the population. Artemisone, a derivative of artemisinin, has shown significant anti-HCMV activity against both laboratory-adapted and low-passage-number clinical strains, including drug-resistant HCMV strains. Artemisone inhibits HCMV replication by reducing viral mRNA accumulation and completely inhibiting viral yield. Its antiviral efficacy consistently surpasses that of artesunate by at least 10-fold.

The antiviral mechanism of artemisinin against HCMV involves several pathways. Firstly, artemisinin and its derivatives interfere with viral replication by inhibiting the nuclear factor (NF)-κB pathway. Artemisinin alkylates the DNA-binding domain of the p65 subunit, inhibiting the binding of specificity protein 1 (SP1) and NF-κB, thereby reducing the activation of very early HCMV promoters and the expression of related genes. Secondly, artemisinin-derived compounds alter the mitochondrial configuration induced by HCMV infection. For instance, BG95, an artemisinin derivative, accumulates in mitochondria, causing dose-dependent changes in mitochondrial structure and reducing mitochondrial membrane potential, which is essential for HCMV replication. Thirdly, immunoprecipitation-mass spectrometry (IP-MS) studies have identified vimentin, a type III intermediate filament protein, as a target of artemisinin against HCMV. Artesunate binding to vimentin stabilizes it and counteracts HCMV-mediated vimentin destabilization, ultimately inhibiting the virus.

Human Herpesvirus 6 (HHV-6)

HHV-6 is a widespread beta-herpesvirus that induces lifelong latent infections in humans. The antiviral activity of artesunate against HHV-6 was demonstrated in a case report of a child with HHV-6B-associated myocarditis. Conventional treatments were ineffective, but intravenous administration of artesunate (5 mg/kg/day) for 10 days, followed by oral therapy (2 × 5 mg/kg) for another 10 days, significantly reduced HHV-6B DNA levels in the myocardium and improved the patient’s clinical status and cardiac function. A comparative study showed that artesunate was more effective than valaciclovir and valganciclovir in treating reactivated HHV-6 infections, with negative polymerase chain reaction (PCR) results achieved in 44%, 57%, and 68% of cases in the first, second, and third months, respectively.

Flaviviridae

The Flaviviridae family includes enveloped positive-strand RNA viruses such as the Japanese encephalitis virus (JEV), Zika virus, hepatitis C virus (HCV), and dengue virus.

Hepatitis C Virus (HCV)

HCV is a single-stranded positive-strand RNA virus with a virion diameter of less than 80 nm. Artesunate inhibits HCV replication in a concentration- and time-dependent manner without adverse effects on host cells. A low dose of IFN combined with a low dose of artesunate achieved the same anti-HCV effect as a high dose of IFN alone. HCV replication activates the nuclear factor E2-related factor 2/antioxidant responsive element (Nrf2/ARE) pathway. Artemisinin combined with heme enhances anti-HCV activity, while the combination with the reactive oxygen species inhibitor N-acetylcysteine significantly reduces it. This suggests that artemisinin and its derivatives generate reactive oxygen species or carbon-centered radicals after the cleavage of the peroxide bridge, regulating the Keap1/Nrf2/ARE pathway and disrupting the HCV replication complex.

Japanese Encephalitis Virus (JEV)

JEV is an 11-kilobase enveloped positive-sense single-stranded RNA virus with five genotypes, all of which can severely affect the central nervous system. In a JEV-infected mouse model, treatment with artemisinin or artesunate reduced mortality rates from 100% to 50% and 60%, respectively. These treatments also diminished astrogliosis, microgliosis, and neuronal cell death in infected mice. In vitro, artemisinin repressed JEV particle production in a concentration-dependent manner, with an IC50 of 18.5 µmol/L. Mechanistically, artemisinin does not block cell binding or virus entry but significantly increases the mRNA expression and secretion of IFN-β and the transcription of interferon-stimulated genes (ISGs), activating interferon regulatory factor 3 (IRF3) and inducing phosphorylation of signal transducers and activators of transcription 1/2 (STAT1/STAT2).

Human Immunodeficiency Virus (HIV)

HIV is a virus that attacks the body’s immune system, primarily by targeting CD4 cells. The interaction of HIV envelope glycoprotein with the primary receptor CD4 and coreceptor allows viral entry and membrane fusion, leading to infection. Several studies have explored the potential anti-HIV activity of artemisinin and its derivatives. Artemisia annua tea infusions inhibited HIV with an IC50 value of 2.9 µg/mL in vitro. Methanol extracts of artemisinin have been shown to inhibit HIV-1 protease activity. A series of artemisinin derivatives with trioxane structures have been synthesized and studied against HIV-1 in vitro, with some showing moderate anti-HIV-1 activity. For example, 10-ethoxy decarbonylation artemisinin and high decarbonization artemisinin exhibited moderate anti-HIV-1 activity. Additionally, six 1,5-disubstituted 1,2,3-triazole derivatives of dihydroartemisinin were synthesized, three of which showed potent anti-HIV activity with IC50 values ranging from 1.34 to 2.65 µmol/L.

Conclusion

Artemisinin and its derivatives have demonstrated antiviral effects against a wide range of viruses, primarily by inhibiting the activation of cellular transcription factors, interfering with the viral replication cycle, inducing cell apoptosis, and preventing virus binding to host cells. However, convincing clinical evidence for the antiviral efficacy of artemisinin is still lacking. Therefore, further clinical trials are encouraged to explore the potential of artemisinin and its derivatives in combating viral infections.

doi.org/10.1097/CM9.0000000000002934

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