Sensitivity of human herpesvirus 6 and other human herpesviruses to the broad-spectrum antiinfective drug artesunate

Milbradt, Jens; Auerochs, Sabrina; Korn, Klaus; Marschall, Manfred

doi:10.1016/j.jcv.2009.05.017

Cited by 60 publications

(40 citation statements)

References 32 publications

(43 reference statements)

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“…It has been proven to inhibit the replication of several human herpesviruses in vitro, in particular HCMV and HHV-6, and has been given to treat HCMV infections in vivo as a compassionate use. Its mechanism of antiviral activity likely involves the modulation of cellular activation pathways involving Sp1 and NF-B (212,213). Valomaciclovir, a drug developed initially against varicella-zoster virus, has also shown significant activity against HHV-6 in vitro (214)(215)(216).…”

Section: Antiviral Agentsmentioning

confidence: 99%

Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections

2015

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SUMMARY Human herpesvirus 6 (HHV-6) is a widespread betaherpesvirus which is genetically related to human cytomegalovirus (HCMV) and now encompasses two different species: HHV-6A and HHV-6B. HHV-6 exhibits a wide cell tropism in vivo and, like other herpesviruses, induces a lifelong latent infection in humans. As a noticeable difference with respect to other human herpesviruses, genomic HHV-6 DNA is covalently integrated into the subtelomeric region of cell chromosomes (ciHHV-6) in about 1% of the general population. Although it is infrequent, this may be a confounding factor for the diagnosis of active viral infection. The diagnosis of HHV-6 infection is performed by both serologic and direct methods. The most prominent technique is the quantification of viral DNA in blood, other body fluids, and organs by means of real-time PCR. Many active HHV-6 infections, corresponding to primary infections, reactivations, or exogenous reinfections, are asymptomatic. However, the virus may be the cause of serious diseases, particularly in immunocompromised individuals. As emblematic examples of HHV-6 pathogenicity, exanthema subitum, a benign disease of infancy, is associated with primary infection, whereas further virus reactivations can induce severe encephalitis cases, particularly in hematopoietic stem cell transplant recipients. Generally speaking, the formal demonstration of the causative role of HHV-6 in many acute and chronic human diseases is difficult due to the ubiquitous nature of the virus, chronicity of infection, existence of two distinct species, and limitations of current investigational tools. The antiviral compounds ganciclovir, foscarnet, and cidofovir are effective against active HHV-6 infections, but the indications for treatment, as well as the conditions of drug administration, are not formally approved to date. There are still numerous pending questions about HHV-6 which should stimulate future research works on the pathophysiology, diagnosis, and therapy of this remarkable human virus.

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Section: Antiviral Agentsmentioning

confidence: 99%

Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections

2015

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“…However, many clinicians would plan for at least 3 weeks of antiviral therapy. 15 Many other compounds that are active against cytomegalovirus, including brincidofovir (CMX-001), 78,79 CMV423, 80 methylenecyclopropane analogs 81 and artesunate 82 have also been reported to inhibit HHV-6 in vitro. Administration of brincidofovir at a single dose of 2 mg/kg led to maximum plasma concentrations of 350 ng/mL 83 that sufficiently exceeds the half-maximum effective concentration of HHV-6B strain 79 without adverse events including changes in hematological or renal functions.…”

Section: Hhv-6 Encephalitis After Allo-hct M Ogata Et Almentioning

confidence: 99%

“…The results of this study are encouraging because they may indicate the effect of currently available agents for high-risk patients, but we also consider that toxicity of PFA limits the practical application of prophylaxis to the wider HCT recipient population. Many other new compounds including brincidofovir, 78,79 methylenecyclopropane analogs 81 or artesunate 82 may be available in the future for preventing HHV-6 encephalitis. A phase 2 trial showed that brincidofovir effectively prevented cytomegalovirus diseases without myelosuppression and nephrotoxicity in allo-HCT recipients.…”

Section: Prevention: We Do Not Know Measures For Preventing Hhv-6 Encmentioning

confidence: 99%

Human herpesvirus-6 encephalitis after allogeneic hematopoietic cell transplantation: What we do and do not know

Ogata

Fukuda²,

Teshima

2015

Bone Marrow Transplant

104

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Human herpesvirus-6 (HHV-6) encephalitis following allogeneic hematopoietic cell transplantation is a serious and often fatal complication accompanying reactivation of HHV-6B. Incidence varies among studies, but is reportedly 0-11.6% after bone marrow or PBSC transplantation and 4.9-21.4% after umbilical cord blood transplantation, typically around 2-6 weeks post transplant. Symptoms are characterized by memory loss, loss of consciousness and seizures. Magnetic resonance imaging (MRI) typically shows bilateral signal abnormalities in the limbic system. This complication is considered to represent acute encephalitis caused by direct virally induced damage to the central nervous system, but our understanding of the etiologies and pathogenesis is still limited. The mortality rate attributable to this pathology remains high, and survivors are often left with serious sequelae such as impaired memory and epilepsy. Despite the poor prognosis, no validated treatments or preventative measures have been established. Establishment of preventative strategies represents an important challenge. This article reviews the current knowledge of the clinical features, incidence, pathogenesis and treatment of HHV-6 encephalitis, and discusses issues needing clarification in the future to overcome this serious complication.

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“…Antiviral assays were established for a selection of human and animal viruses used for the infection of a set of different primary and immortalized cells types as described earlier (13,20,22,(24)(25)(26)(27). Specifically, a green fluorescent protein (GFP)-based viral replication assay was performed with HCMV AD169-GFP in HFFs as previously described (13).…”

Section: Methodsmentioning

confidence: 99%

“…Assays measuring distinct parameters of cytotoxicity and/or cell proliferation were performed as described earlier (25,27). In brief, a trypan blue exclusion assay was performed with cultured cells seeded in 24-well plates and incubated with increasing concentrations of antiviral compounds (range, 0.1 to 50 M) for the durations indicated.…”

Section: Methodsmentioning

confidence: 99%

A Novel CDK7 Inhibitor of the Pyrazolotriazine Class Exerts Broad-Spectrum Antiviral Activity at Nanomolar Concentrations

Hutterer

Eickhoff

Milbradt

et al. 2015

Antimicrob Agents Chemother

Self Cite

123

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bProtein kinases represent central and multifunctional regulators of a balanced virus-host interaction. Cyclin-dependent protein kinase 7 (CDK7) plays crucial regulatory roles in cell cycle and transcription, both connected with the replication of many viruses. Previously, we developed a CDK7 inhibitor, LDC4297, that inhibits CDK7 in vitro in the nano-picomolar range. Novel data from a kinome-wide evaluation (>330 kinases profiled in vitro) demonstrate a kinase selectivity. Importantly, we provide first evidence for the antiviral potential of the CDK7 inhibitor LDC4297, i.e., in exerting a block of the replication of human cytomegalovirus (HCMV) in primary human fibroblasts at nanomolar concentrations (50% effective concentration, 24.5 ؎ 1.3 nM). As a unique feature compared to approved antiherpesviral drugs, inhibition occurred already at the immediate-early level of HCMV gene expression. The mode of antiviral action was considered multifaceted since CDK7-regulated cellular factors that are supportive of HCMV replication were substantially affected by the inhibitors. An effect of LDC4297 was identified in the interference with HCMV-driven inactivation of retinoblastoma protein (Rb), a regulatory step generally considered a hallmark of herpesviral replication. In line with this finding, a broad inhibitory activity of the drug could be demonstrated against a selection of human and animal herpesviruses and adenoviruses, whereas other viruses only showed intermediate drug sensitivity. Summarized, the CDK7 inhibitor LDC4297 is a promising candidate for further antiviral drug development, possibly offering new options for a comprehensive approach to antiviral therapy. C yclin-dependent kinases (CDKs) are characterized as regulators of two major transitions in the cell cycle, namely, the initiation of the DNA synthesis (S) phase and the entry into mitosis (M) phase. CDKs are generally coregulated in activity by their interaction with distinct types or a selection of cyclins. In addition to cell cycle control, CDK/cyclin complexes have also been identified as conserved components of the RNA polymerase II (RNAP II) transcriptional machinery (1). CDK7 is both a CDK-activating kinase (CAK), which phosphorylates CDKs within the activation segment (T-loop), and a component of the transcription factor TFIIH, which phosphorylates the C-terminal domain (CTD) of RNAP II (2-5). This central importance of CDK7 has long been asserted as an essential role in cellular metabolism and viability. Recently, a study by Ganuza et al. (6) demonstrated that depletion of CDK7 in vivo had no phenotypic consequences in adult tissues with low proliferative indexes and that CDK7 is mostly dispensable for transcriptional regulation. In contrast, CDK7 activity appears basically essential for cell cycle activation via phosphorylation of CDKs, primarily CDK1 and CDK2, and genetic inactivation of CDK7 leads to cell cycle arrest in tissues with elevated cellular turnover. Thus, CDK7-related defects may not be universally expressed, but can be restric...

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Sensitivity of human herpesvirus 6 and other human herpesviruses to the broad-spectrum antiinfective drug artesunate

Cited by 60 publications

References 32 publications

Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections

Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections

Human herpesvirus-6 encephalitis after allogeneic hematopoietic cell transplantation: What we do and do not know

A Novel CDK7 Inhibitor of the Pyrazolotriazine Class Exerts Broad-Spectrum Antiviral Activity at Nanomolar Concentrations

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