Stability and antiviral activity against human cytomegalovirus of artemisinin derivatives

Flobinus, Alyssa; Taudon, Nicolas; Desbordes, Marc; Labrosse, Béatrice; Simon, François; Mazeron, Marie‐Christine; Schnepf, Nathalie

doi:10.1093/jac/dkt346

Cited by 49 publications

(32 citation statements)

References 32 publications

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“…Similar to the 65% reduction of the extracellular BKPyV load found in RPTECs (39), 10 M artesunate reduced the extracellular JCPyV DNA load by 75%, and this correlated with a decrease in the number of VP1-expressing cells and in infectious progeny release. The EC 50 of 2.9 M was in the same range as that found for BKPyV (4.2 M) (39) and for herpesviruses (2.16 to 7.21 M) (29,31,(50)(51)(52), although different host cells were used. Artesunate affects a very early stage of herpesvirus infection, but the mechanism seems to be the inhibition of cellular pathways (50).…”

Section: Discussionsupporting

confidence: 58%

Antiviral Effects of Artesunate on JC Polyomavirus Replication in COS-7 Cells

Sharma

Marschall

Rinaldo

2014

Antimicrob Agents Chemother

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The human JC polyomavirus (JCPyV) causes the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). A growing number of patients with induced or acquired immunosuppression are at risk for infection, and no effective antiviral therapy is presently available. The widely used antimalarial drug artesunate has shown broad antiviral activity in vitro but limited clinical success. The aim of this study was to investigate the effect of artesunate on JCPyV replication in vitro. The permissivity for JCPyV MAD-4 was first compared in four cell lines, and the monkey kidney cell line COS-7 was selected. Artesunate caused a concentration-dependent decrease in the extracellular JCPyV DNA load 96 h postinfection, with a 50% effective concentration (EC 50 ) of 2.9 M. This effect correlated with a decreased expression of capsid protein VP1 and a reduced release of infectious viral progeny. For concentrations of <20 M, transient reductions in cellular DNA replication and proliferation were seen, while for higher concentrations, some cytotoxicity was detected. A selective index of 16.6 was found when cytotoxicity was calculated based on cellular DNA replication in the mock-infected cells, but interestingly, cellular DNA replication in the JCPyV-infected cells was more strongly affected. In conclusion, artesunate is efficacious in inhibiting JCPyV replication at micromolar concentrations, which are achievable in plasma. The inhibition at EC 50 probably reflects an effect on cellular proteins and involves transient cytostatic effects. Our results, together with the favorable distribution of the active metabolite dihydroartemisinin to the central nervous system, suggest a potential use for artesunate in patients with PML.

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Section: Discussionsupporting

confidence: 58%

Antiviral Effects of Artesunate on JC Polyomavirus Replication in COS-7 Cells

Sharma

Marschall

Rinaldo

2014

Antimicrob Agents Chemother

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“…ART, dihydroartemisinin (DHA) and artesunate (AS) were compared for their anti-HCMV effect in a fibroblast cell model by measuring viral DNA synthesis in cellular lysates. ART showed the lowest activity, even when fractional doses and daily repeated administration were used to counteract the problem of instability of the compounds in a culture medium [16]. Compared to other compounds from traditional Chinese medicine, ART and AS were also the most active, with low toxicity, for the inhibition of the hepatitis B virus (HBV), measured by hepatitis B surface antigen (HBsAg) and DNA release in a culture medium.…”

Section: Artemisininmentioning

confidence: 99%

“…The activity of AS on the replication of HCMV was demonstrated in different in vitro cell models, such as fibroblasts [11,16,24] and tumor cells [25,26]. Compared to other ART derivatives, AS had the highest activity [16,27] and an activity comparable to or even higher than that of classical antiviral drugs, such as ganciclovir [16,25,28].…”

Section: Artesunate and Hcmvmentioning

confidence: 99%

The Use of Antimalarial Drugs against Viral Infection

et al. 2020

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In recent decades, drugs used to treat malaria infection have been shown to be beneficial for many other diseases, including viral infections. In particular, they have received special attention due to the lack of effective antiviral drugs against new emerging viruses (i.e., HIV, dengue virus, chikungunya virus, Ebola virus, etc.) or against classic infections due to drug-resistant viral strains (i.e., human cytomegalovirus). Here, we reviewed the in vitro/in vivo and clinical studies conducted to evaluate the antiviral activities of four classes of antimalarial drugs: Artemisinin derivatives, aryl-aminoalcohols, aminoquinolines, and antimicrobial drugs.

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“…A rtemisinins, drugs of choice for malaria therapy, inhibit human cytomegalovirus (CMV) replication (1)(2)(3)(4). Artesunate (AS) and the parent compound artemisinin inhibit CMV replication in vitro and in vivo.…”

mentioning

confidence: 99%

Inhibition of Human Cytomegalovirus Replication by Artemisinins: Effects Mediated through Cell Cycle Modulation

Roy

Kapoor

et al. 2015

Antimicrob Agents Chemother

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dArtemisinin-derived monomers and dimers inhibit human cytomegalovirus (CMV) replication in human foreskin fibroblasts (HFFs). The monomer artesunate (AS) inhibits CMV at micromolar concentrations, while dimers inhibit CMV replication at nanomolar concentrations, without increased toxicity in HFFs. We report on the variable anti-CMV activity of AS compared to the consistent and reproducible CMV inhibition by dimer 606 and ganciclovir (GCV). Investigation of this phenomenon revealed that the anti-CMV activity of AS correlated with HFFs synchronized to the G 0 /G 1 stage of the cell cycle. In contact-inhibited serum-starved HFFs or cells arrested at early/late G 1 with specific checkpoint regulators, AS and dimer 606 efficiently inhibited CMV replication. However, in cycling HFFs, in which CMV replication was productive, virus inhibition by AS was significantly reduced, but inhibition by dimer 606 and GCV was maintained. Cell cycle analysis in noninfected HFFs revealed that AS induced early G 1 arrest, while dimer 606 partially blocked cell cycle progression. In infected HFFs, AS and dimer 606 prevented the progression of cell cycle toward the G 1 /S checkpoint. AS reduced the expression of cyclin-dependent kinases (CDK) 2, 4, and 6 in noninfected cycling HFFs, while the effect of dimer 606 on these CDKs was moderate. Neither compound affected CDK expression in noninfected contact-inhibited HFFs. In CMV-infected cells, AS activity correlated with reduced CDK2 levels. CMV inhibition by AS and dimer 606 also correlated with hypophosphorylation (activity) of the retinoblastoma protein (pRb). AS activity was strongly associated with pRb hypophosphorylation, while its reduced anti-CMV activity was marked by pRb phosphorylation. Roscovitine, a CDK2 inhibitor, antagonized the anti-CMV activities of AS and dimer 606. These data suggest that cell cycle modulation through CDKs and pRb might play a role in the anti-CMV activities of artemisinins. Proteins involved in this modulation may be identified and targeted for CMV inhibition.A rtemisinins, drugs of choice for malaria therapy, inhibit human cytomegalovirus (CMV) replication (1-4). Artesunate (AS) and the parent compound artemisinin inhibit CMV replication in vitro and in vivo. Variable responses to AS in case reports of CMV-infected patients have been attributed to the dosing regimen, duration of therapy, or tissue penetration of AS (5-8). In our effort to improve and uncover the anti-CMV activities of artemisinins, we reported on in vitro highly selective inhibition of CMV replication with artemisinin-derived dimers, significantly more than with their monomeric counterparts, without increasing toxicity in human foreskin fibroblasts (HFFs) (3, 9). Although similar effects on CMV replication were observed between monomers and dimers (timing of CMV inhibition, effects on DNA replication, and virus yield), dimers inhibited CMV at nanomolar concentrations and had a high slope of the dose-response curve, a measure of cooperativity in binding of multiple ligands to linked bi...

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Stability and antiviral activity against human cytomegalovirus of artemisinin derivatives

Abstract: Artemisinin derivatives were shown to be unstable in vitro and their addition as fractional doses could partly compensate for this instability. Importantly, the cellular physiological condition was a determinant of their antiviral activity.

Cited by 49 publications

References 32 publications

Antiviral Effects of Artesunate on JC Polyomavirus Replication in COS-7 Cells

Antiviral Effects of Artesunate on JC Polyomavirus Replication in COS-7 Cells

The Use of Antimalarial Drugs against Viral Infection

Inhibition of Human Cytomegalovirus Replication by Artemisinins: Effects Mediated through Cell Cycle Modulation

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