Inhibition of B virus (Macacine herpesvirus 1) by conventional and experimental antiviral compounds.

Viral Immunology Center, Georgia State University, P.O. Box 4118, Atlanta, GA 30302, USA.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.45). 10/2009; 54(1):452-9. DOI: 10.1128/AAC.01435-08
Source: PubMed

ABSTRACT B virus infection of humans results in high morbidity and mortality in as many as 80% of identified cases. The main objective of this study was to conduct a comparative analysis of conventional and experimental antiviral drug susceptibilities of B virus isolates from multiple macaque species and zoonotically infected humans. We used a plaque reduction assay to establish the effective inhibitory doses of acyclovir, ganciclovir, and vidarabine, as well as those of a group of experimental nucleoside analogs with known anti-herpes simplex virus activity. Four of the experimental drugs tested were 10- to 100-fold more potent inhibitors of B virus replication than conventional antiviral agents. Drug efficacies were similar for multiple B virus isolates tested, with variations within 2-fold of the median effective concentration (EC(50)) for each drug, and each EC(50) was considerably lower than those for B virus thymidine kinase (TK) mutants. We observed no differences in the viral TK amino acid sequence between B virus isolates from rhesus monkeys and those from human zoonoses. Differences in the TK protein sequence between cynomolgus and pigtail macaque B virus isolates did not affect drug sensitivity except in the case of one compound. Taken together, these data suggest that future B virus zoonoses will respond consistently to conventional antiviral treatment. Further, the considerably higher potency of FEAU (2'-fluoro-5-ethyl-Ara-U) than of conventional antiviral drugs argues for its compassionate use in advanced human B virus infections.

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    ABSTRACT: Introduction: Although a number of antiviral agents are licensed for treatment of some human herpesvirus (HHV) infections, effective antiviral therapy is not available for all HHVs. Additional complications are associated with approved drugs, such as toxicity and side effects, and rise in drug-resistant strains is a driving force for new drug development. Success in HHV vaccine development is limited with only vaccines against varicella-zoster virus currently in use in the clinic. In vitro, in vivo and in silico high-throughput (HTP) approaches and innovative microfluidic systems will provide novel technologies to efficiently identify and evaluate new targets and antiherpetic compounds. Coupled with HTP strategies for manipulation of herpesvirus viral genomes, these strategies will greatly accelerate the development of future antivirals as well as candidate vaccine intervention strategies. Areas covered: The authors provide a brief overview of the herpesvirus family and associated diseases. Further, the authors discuss the approved and investigational antiherpetic drugs in the context of current HTP technologies. Expert opinion: HTP technology such as microfluidic systems is crucial for the identification and validation of novel drug targets and next-generation antivirals. Current drug development is limited by the unavailability of HTP preclinical model systems. Specific advancement in the development of HTP animal-specific technology, applied in parallel, allows a more rapid evaluation of drugs at the preclinical stage. The advancement of HTP combinatorial drug therapy, especially 'Organ-on-a-Chip' approaches, will aid in the evaluation of future antiviral compounds and intervention strategies.
    Expert Opinion on Drug Discovery 07/2014; DOI:10.1517/17460441.2014.922538 · 3.47 Impact Factor

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