A highly potent trimeric derivative of artesunate shows promising treatment profiles in experimental models for congenital HCMV infection in vitro and ex vivo

Jacquet, Chloé; Marschall, Manfred; Andouard, D.; Hamel, Charhazed El; Chianea, Thierry; Tsogoeva, Svetlana B.; Hantz, Sébastien; Alain, Sophie

doi:10.1016/j.antiviral.2019.104700

Cited by 14 publications

(17 citation statements)

References 46 publications

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“…Based on our combined findings, we postulate a mitochondrial targeting of BG95 and related derivatives possessing pronounced antiviral efficacies both in vitro and in vivo [ 20 , 49 , 51 , 61 , 68 , 98 , 99 ].…”

Section: Discussionmentioning

confidence: 97%

The Artemisinin-Derived Autofluorescent Compound BG95 Exerts Strong Anticytomegaloviral Activity Based on a Mitochondrial Targeting Mechanism

Wild

Hahn

Grau³

et al. 2020

IJMS

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Human cytomegalovirus (HCMV) is a major human pathogen associated with severe pathology. Current options of antiviral therapy only partly satisfy the needs of a well-tolerated long-term treatment/prophylaxis free from drug-induced viral resistance. Recently, we reported the strong antiviral properties in vitro and in vivo of the broad-spectrum anti-infective drug artesunate and its optimized derivatives. NF-κB signaling was described as a targeting mechanism and additional target proteins have recently been identified. Here, we analyzed the autofluorescent hybrid compound BG95, which could be utilized for intracellular visualization by confocal imaging and a tracking analysis in virus-infected primary human fibroblasts. As an important finding, BG95 accumulated in mitochondria visualized by anti-prohibitin and MitoTracker staining, and induced statistically significant changes of mitochondrial morphology, distinct from those induced by HCMV infection. Notably, mitochondrial membrane potential was found substantially reduced by BG95, an effect apparently counteracting efficient HCMV replication, which requires active mitochondria and upregulated energy levels. This finding was consistent with binding properties of artesunate-like compounds to mitochondrial proteins and thereby suggested a new mechanistic aspect. Combined, the present study underlines an important role of mitochondria in the multifaceted, host-directed antiviral mechanism of this drug class, postulating a new mitochondria-specific mode of protein targeting.

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Section: Discussionmentioning

confidence: 97%

The Artemisinin-Derived Autofluorescent Compound BG95 Exerts Strong Anticytomegaloviral Activity Based on a Mitochondrial Targeting Mechanism

Wild

Hahn

Grau³

et al. 2020

IJMS

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“…Human infection with the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID- 19), which was declared as a pandemic by the World Health Organization on 11 March 2020. Besides the ongoing development of drug candidates directed against viral targets, such as the authorized drug remdesivir, the concept of developing novel host-cell-directed antivirals (HDAs), which potentially exert broad-spectrum antiviral activity independent of viral mutations appears particularly promising [16][17][18][19][20][21][22][23][24][25][26][27][28][29]. Such purposeful drug profiles, which for some HDAs span over other anti-infective, antitumor and immunoregulatory activities, are considered to be particularly powerful to combat emerging viral diseases such as COVID-19.…”

Section: Introductionmentioning

confidence: 99%

IMU-838, a Developmental DHODH Inhibitor in Phase II for Autoimmune Disease, Shows Anti-SARS-CoV-2 and Broad-Spectrum Antiviral Efficacy In Vitro

Hahn

Wangen

Häge

et al. 2020

Viruses

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The ongoing pandemic spread of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) demands skillful strategies for novel drug development, drug repurposing and cotreatments, in particular focusing on existing candidates of host-directed antivirals (HDAs). The developmental drug IMU-838, currently being investigated in a phase 2b trial in patients suffering from autoimmune diseases, represents an inhibitor of human dihydroorotate dehydrogenase (DHODH) with a recently proven antiviral activity in vitro and in vivo. Here, we established an analysis system for assessing the antiviral potency of IMU-838 and DHODH-directed back-up drugs in cultured cell-based infection models. By the use of SARS-CoV-2-specific immunofluorescence, Western blot, in-cell ELISA, viral yield reduction and RT-qPCR methods, we demonstrated the following: (i) IMU-838 and back-ups show anti-SARS-CoV-2 activity at several levels of viral replication, i.e., protein production, double-strand RNA synthesis, and release of infectious virus; (ii) antiviral efficacy in Vero cells was demonstrated in a micromolar range (IMU-838 half-maximal effective concentration, EC50, of 7.6 ± 5.8 µM); (iii) anti-SARS-CoV-2 activity was distinct from cytotoxic effects (half-cytotoxic concentration, CC50, >100 µM); (iv) the drug in vitro potency was confirmed using several Vero lineages and human cells; (v) combination with remdesivir showed enhanced anti-SARS-CoV-2 activity; (vi) vidofludimus, the active determinant of IMU-838, exerted a broad-spectrum activity against a selection of major human pathogenic viruses. These findings strongly suggest that developmental DHODH inhibitors represent promising candidates for use as anti-SARS-CoV-2 therapeutics.

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“…When compared with ART, TF27 showed higher in vitro efficacy against HCMV replication against AD169 strain, endotheliotropic strains VHL/E and TB40/E, and clinical strain S * . The EC 50 values of TF27 were in the nanomolar range, while those of ART were in the micromolar range [ 85 ].…”

Section: Malaria and Its Parasite Life Cyclementioning

confidence: 99%

“…HCMV strains AD169, TB40/E, and VHL/E infected placental villi, with AD169 strain reaching a peak of 2.6 × 10 6 viral copies per million cells after incubation for 10 days and was stable at day 13. Both ART and TF27 significantly decreased viral load in the first-trimester placenta explants, with TF27 showing EC 50 values 200-fold lower than that of ART, making it a potential candidate for congenital HCMV treatment [ 85 ].…”

Section: Malaria and Its Parasite Life Cyclementioning

confidence: 99%

Recent Advances in the Therapeutic Efficacy of Artesunate

2022

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Artesunate, a semisynthetic artemisinin derivative, is well-known and used as the first-line drug for treating malaria. Apart from treating malaria, artesunate has also been found to have biological activity against a variety of cancers and viruses. It also exhibits antidiabetic, anti-inflammatory, anti-atherosclerosis, immunosuppressive activities, etc. During its administration, artesunate can be loaded in liposomes, alone or in combination with other therapeutic agents. Administration routes include intragastrical, intravenous, oral, and parenteral. The biological activity of artesunate is based on its ability to regulate some biological pathways. This manuscript reports a critical review of the recent advances in the therapeutic efficacy of artesunate.

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A highly potent trimeric derivative of artesunate shows promising treatment profiles in experimental models for congenital HCMV infection in vitro and ex vivo

Cited by 14 publications

References 46 publications

The Artemisinin-Derived Autofluorescent Compound BG95 Exerts Strong Anticytomegaloviral Activity Based on a Mitochondrial Targeting Mechanism

The Artemisinin-Derived Autofluorescent Compound BG95 Exerts Strong Anticytomegaloviral Activity Based on a Mitochondrial Targeting Mechanism

IMU-838, a Developmental DHODH Inhibitor in Phase II for Autoimmune Disease, Shows Anti-SARS-CoV-2 and Broad-Spectrum Antiviral Efficacy In Vitro

Recent Advances in the Therapeutic Efficacy of Artesunate

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