Inhibition of murine cytomegalovirus and human cytomegalovirus by a novel non-nucleosidic compound in vivo

Weber, Olaf; Bender, Wolfgang; Eckenberg, Peter; Goldmann, Siegfried; Haerter, Michael; Hallenberger, Sabine; Henninger, Kerstin; Reefschläger, J; Trappe, Jörg; Witt‐Laido, Astrid; Ruebsamen‐Waigmann, Helga

doi:10.1016/s0166-3542(01)00127-9

Cited by 34 publications

(26 citation statements)

References 27 publications

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“…Current research has led to the discovery of several novel compounds with in vitro and in vivo activities against HCMV (6,7,16). One such compound, BAY38-4766, is a nonnucleosidic inhibitor of HCMV replication (17). Two phenotypic drug susceptibility assays, a flow cytometric fluorescence-activated cell sorter (FACS) assay (8-10) and a plaque reduction assay (PRA) (15), were used to compare the effects of BAY38-4766, its main metabolite, BAY43-9695, and ganciclovir on the in vitro replication of ganciclovir-susceptible and ganciclovir-resistant HCMV clinical isolates.…”

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confidence: 99%

Susceptibilities of Human Cytomegalovirus Clinical Isolates to BAY38-4766, BAY43-9695, and Ganciclovir

McSharry

McDonough

Olson

et al. 2001

Antimicrob Agents Chemother

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BAY38-4766 and BAY43-9695 are nonnucleosidic compounds with activities against human cytomegalovirus (HCMV). Two phenotypic assays were used to determine the drug susceptibilities of 36 HCMV clinical isolates to the BAY compounds and ganciclovir. Using either assay, both BAY compounds at a concentration of approximately 1 M inhibited the replication of all 36 HCMV clinical isolates, including 11 ganciclovirresistant clinical isolates, by 50%.Human cytomegalovirus (HCMV) causes considerable morbidity and mortality in immunocompromised hosts (13). Organ transplant patients suffer from hepatitis and pneumonia caused by HCMV infections, whereas AIDS patients suffer from HCMV-induced retinitis and other complications (1). The current Food and Drug Administration-approved therapies for retinitis due to infection with HCMV include ganciclovir, foscarnet, cidofovir, and fomivirsen (2,11,12,14). These antiviral drugs are active against infections caused by HCMV; however, they are not ideal because of their toxicity and poor bioavailability. Furthermore, long-term treatment with these antiviral agents often leads to the selection of viral mutants that are resistant to one or more of these drugs (3-5). Current research has led to the discovery of several novel compounds with in vitro and in vivo activities against HCMV (6, 7, 16). One such compound, BAY38-4766, is a nonnucleosidic inhibitor of HCMV replication (17). Two phenotypic drug susceptibility assays, a flow cytometric fluorescence-activated cell sorter (FACS) assay (8-10) and a plaque reduction assay (PRA) (15), were used to compare the effects of BAY38-4766, its main metabolite, BAY43-9695, and ganciclovir on the in vitro replication of ganciclovir-susceptible and ganciclovir-resistant HCMV clinical isolates. BAY38-4766 and BAY43-9695 inhibited the replication of ganciclovir-sensitive and ganciclovirresistant HCMV clinical isolates at concentrations less than or equal to 1 M. These results suggest that these compounds are potentially useful for treating patients infected with ganciclovir-sensitive or ganciclovir-resistant HCMV.The use of the FACS assay and the PRA for determining 50% inhibitory concentrations (IC 50 s) for HCMV clinical isolates have been described in detail previously (8-10). These two phenotypic assays were used to determine the susceptibilities of the AD169 laboratory strain of HCMV and 36 HCMV clinical isolates to BAY38-4766, BAY43-9695, and ganciclovir. The FACS assay yielded average IC 50 s of BAY38-4766, BAY43-9695, and ganciclovir for the AD169 laboratory strain of 0.95 Ϯ 0.17 (mean Ϯ standard deviation), 0.70 Ϯ 0.30, and 3.05 Ϯ 0.21 M, respectively. The PRA yielded average IC 50 s of these three drugs for AD169 of 0.64 Ϯ 0.14, 0.55 Ϯ 0.06, and 3.50 Ϯ 0.21 M, respectively. The average IC 50 s of the two BAY compounds and ganciclovir for 36 HCMV clinical isolates are presented in Table 1. Both BAY compounds inhibited the replication of all of the HCMV clinical isolates by 50% at essentially the same concentrations. Of the 36 HCMV clinical i...

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confidence: 99%

Susceptibilities of Human Cytomegalovirus Clinical Isolates to BAY38-4766, BAY43-9695, and Ganciclovir

McSharry

McDonough

Olson

et al. 2001

Antimicrob Agents Chemother

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“…It is found to be highly active against CMV in vitro [48]. This molecule exhibited anti-CMV activity similar to GCV in an immunodeficient mouse model [49]. The compound is active against strains resistant to currently approved anti-CMV drugs.…”

Section: New Anti-cmv Drugsmentioning

confidence: 99%

Current and Emerging Antivirals for the Treatment of Cytomegalovirus (CMV) Retinitis: an Update on Recent Patents

Vadlapudi

Vadlapatla

Mitra

2012

PRI

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Cytomegalovirus (CMV) retinitis is the most common ocular opportunistic complication and a serious cause of vision loss in immunocompromised patients. Even though, a rise in human immunodeficiency virus (HIV) infected individuals seems to be a major factor responsible for the prevalence of CMV retinitis, the introduction of highly active antiretroviral therapy (HAART) significantly reduced the incidence and severity of CMV retinitis. Thorough evaluation of the patient’s immune status and an exact classification of the retinal lesions may provide better understanding of the disease etiology, which would be necessary for optimizing the treatment conditions. Current drugs such as ganciclovir, valganciclovir, cidofovir and foscarnet have been highly active against CMV, but prolonged therapy with these approved drugs is associated with dose-limiting toxicities thus limiting their utility. Moreover development of drug-resistant mutants has been observed particularly in patients with acquired immunodeficiency syndrome (AIDS). Continuous efforts by researchers in the industry and academia have led to the development of newer candidates with enhanced antiviral efficacy and apparently minimal side effects. These novel compounds can suppress viral replication and prevent reactivation in the target population. Though some of the novel therapeutics possess potent viral inhibitory activity, these compounds are still in stages of clinical development and yet to be approved. This review provides an overview of disease etiology, existing anti-CMV drugs, advances in emerging therapeutics in clinical development and related recent patents for the treatment of CMV retinitis.

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“…BAY 38-4766 is effective in both mouse and guinea pig animal models [179, 180] and resistant strains can be isolated that have modifications to the UL89 homolog gene (M89 or GP89). Other more recent CMV terminase antivirals have not been tested in the guinea pig.…”

Section: CMV Antivirals and Animal Modelsmentioning

confidence: 99%

Cytomegalovirus antivirals and development of improved animal models

McGregor

Choi

2011

Expert Opinion on Drug Metabolism & Toxicology

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Introduction Cytomegalovirus (CMV) is a ubiquitous pathogen that establishes a life long asymptomatic infection in healthy individuals. Infection of immunesuppressed individuals causes serious illness. Transplant and AIDS patients are highly susceptible to CMV leading to life threatening end organ disease. Another vulnerable population is the developing fetus in utero, where congenital infection can result in surviving newborns with long term developmental problems. There is no vaccine licensed for CMV and current antivirals suffer from complications associated with prolonged treatment. These include drug toxicity and emergence of resistant strains. There is an obvious need for new antivirals. Candidate intervention strategies are tested in controlled pre-clinical animal models but species specificity of HCMV precludes the direct study of the virus in an animal model. Areas covered This review explores the current status of CMV antivirals and development of new drugs. This includes the use of animal models and the development of new improved models such as humanized animal CMV and bioluminescent imaging of virus in animals in real time. Expert Opinion Various new CMV antivirals are in development, some with greater spectrum of activity against other viruses. Although the greatest need is in the setting of transplant patients there remains an unmet need for a safe antiviral strategy against congenital CMV. This is especially important since an effective CMV vaccine remains an elusive goal. In this capacity greater emphasis should be placed on suitable pre-clinical animal models and greater collaboration between industry and academia.

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Inhibition of murine cytomegalovirus and human cytomegalovirus by a novel non-nucleosidic compound in vivo

Cited by 34 publications

References 27 publications

Susceptibilities of Human Cytomegalovirus Clinical Isolates to BAY38-4766, BAY43-9695, and Ganciclovir

Susceptibilities of Human Cytomegalovirus Clinical Isolates to BAY38-4766, BAY43-9695, and Ganciclovir

Current and Emerging Antivirals for the Treatment of Cytomegalovirus (CMV) Retinitis: an Update on Recent Patents

Cytomegalovirus antivirals and development of improved animal models

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