Phosphorescent rhenium(I) complexes conjugated with artesunate: Mitochondrial targeting and apoptosis-ferroptosis dual induction.

Cell death is essential for cancer, which can be induced through multiple mechanisms. Ferroptosis, a newly emerging form of non-apoptotic cell death, involves the generation of iron-dependent reactive oxygen species (ROS). In this study, we designed and synthesized two artesunate (ART) conjugated phosphorescent rhenium(I) complexes (Re(I)-ART conjugates), [Re(N^N)(CO)3(PyCH2OART)](PF6) (Re-ART-1 and Re-ART-2) (Py = pyridine, N^N = 1,10-phenanthroline (phen, in Re-ART-1) and 4,7-diphenyl-1,10-phenanthroline (DIP, in Re-ART-2)) that can specifically locate in the mitochondria of human cervical carcinoma (HeLa). Mechanism studies show that Re-ART-1 and Re-ART-2 exhibit high cytotoxicity against cancer cells lines and can induce both apoptosis and ferroptosis in HeLa cells through mitochondrial damage, caspase cascade, glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4) inactivation and lipid peroxidation accumulation. As a result, this work presents the rational design of Re(I)-ART conjugates as a promising strategy to induce both apoptosis and ferroptosis and improve therapeutic efficiency of cancer treatment.

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

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.

The trimeric artesunate derivative TF27 exerts strong anti-cytomegaloviral efficacy: Focus on prophylactic efficacy and oral treatment of immunocompetent mice.

Human cytomegalovirus (HCMV) causes serious and even life-threatening diseases, particularly upon congenital or post-transplant infection. Treatment of HCMV infections with currently available drugs targeting viral enzymes is often limited by severe side effects and the emergence of drug-resistant viruses. To avoid this problem, novel therapeutic options directed to host proteins involved in virus replication are being investigated. Recently, we described the pronounced antiherpesviral activity of the trimeric artesunate derivative TF27 at low nanomolar concentrations in vitro and in vivo. In the present study, we report first data on the prophylactic efficacy of TF27 against human and murine CMV and the oncogenic avian alphaherpesvirus Marek's disease virus (MDV). The main findings of this study are (i) a pronounced activity of the experimental drug TF27 against alpha- and betaherpesviruses in vitro upon prophylactic treatment and (ii) a therapeutic and prophylactic efficacy upon oral treatment in an immunocompetent mouse model. Moreover, our data highlight (iii) the tolerability of orally administered TF27 free of compound-associated adverse events and further confirm (iv) the suitability of cellular factors as primary antiviral targets. Thus, we provide evidence for therapeutic and prophylactic antiherpesviral efficacy of TF27 upon oral treatment in immunocompetent hosts and thereby underline its potential for future antiviral drug development.

Artesunate derivative TF27 inhibits replication and pathogenesis of an oncogenic avian alphaherpesvirus.

Nucleoside analogues have been the cornerstone of clinical treatment of herpesvirus infections since the 1970s. However, severe side effects and emergence of drug resistant viruses raise the need for alternative treatment options. We recently investigated the broad and strong antiherpesviral activity of the optimized artesunate derivative TF27 in vitro. TF27 efficiently inhibited replication of the highly oncogenic Marek's disease virus (MDV), a virus that infects chickens, causes deadly lymphomas and threatens poultry populations worldwide. In this study, we used this natural virus-host model for herpesvirus-induced cancer by infecting chickens with MDV, and evaluated the protective efficacy of TF27 and the nucleoside analogue valganciclovir (VGCV) on virus replication and tumorigenesis. We could demonstrate that both drugs reduced viral load in the blood and prevented tumor development in a large portion of the animals. Antiviral treatment also had a positive impact on body weight gain, while no negative compound-associated side effects were observed. This research provides the first evidence that the artesunate derivative TF27 and VGCV can be used in avian species and that they inhibit MDV replication and tumorigenesis. In addition, our study paves the way for promising approaches in future antiherpesviral drug development.