Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of trisodium phosphonoformate (PFA) has been compared to that of idoxuridine (IDU) when applied topically in both liquid and ointment preparations on herpetic keratitis in rabbits. Trisodium phosphonoformate had a therapeutic effect but was not as effective as idoxuridine in the vehicles tested. This was seen with both herpes-immunized and non-immunized rabbits. A herpesvirus mutant inducing a PFA restant DNA polymerase was used to infect rabbit corneas. A comparison of the effect of PFA on the keratitis caused by this resistant mutant and the wild type herpesvirus indicates that the therapeutic effect of PFA on the herpes keratitis was due to an inhibition of herpesvirus DNA polymerase.
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PMID:Effect of trisodium phosphonoformate and idoxuridine on experimental herpes simplex keratitis in immunized and non-immunized rabbits. 624 66

Feline herpes virus-1 (FHV-1) is ubiquitous in the cat population and is a major cause of blindness for which antiviral drugs, including acyclovir, are not completely effective. Recurrent infections, due to reactivation of latent FHV-1 residing in the trigeminal ganglia, can lead to epithelial keratitis and stromal keratitis and eventually loss of sight. This has prompted the medical need for an antiviral drug that will specifically inhibit FHV-1 infection. A new antiviral target is the DNA polymerase and its associated processivity factor, which forms a complex that is essential for extended DNA strand synthesis. In this study we have cloned and expressed the FHV-1 DNA polymerase (f-UL30) and processivity factor (f-UL42) and demonstrated that both proteins are required to completely synthesize the 7249 nucleotide full-length DNA from the M13 primed-DNA template in vitro. Significantly, a known inhibitor of human herpes simplex virus-1 (HSV-1) processivity complex was shown to inhibit FHV-1 processive DNA synthesis in vitro and block infection of cells. This validates using f-UL42/f-UL30 as a new antiviral drug target to treat feline ocular herpes infection.
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PMID:The processivity factor complex of feline herpes virus-1 is a new drug target. 2554 73

Anti-microbial compounds typically exert their action by directly interfering with one or more stages of the pathogen's life cycle. However, some compounds also have secondary effects on the host that aid in pathogen clearance. Raltegravir is a human immunodeficiency virus (HIV)-integrase inhibitor that has been shown to alter the host immune response to HIV in addition to its direct antiviral effect. Interestingly, raltegravir can also directly inhibit the replication of various herpesviruses. However, the host-targeted effects of this drug in the context of a herpesvirus infection have not been explored. Here, we used felid alphaherpesvirus 1 (FHV-1), a close relative of human alphaherpesvirus 1 (HHV-1) that similarly causes ocular herpes, to characterize the host-targeted effects of raltegravir on corneal epithelial cells during an alphaherpesvirus infection. Using RNA deep sequencing, we found that raltegravir specifically boosts the expression of anti-angiogenic factors and promotes metabolic homeostasis in FHV-1-infected cells. In contrast, few changes in host gene transcription were found in uninfected cells. Importantly, we were able to demonstrate that these effects were specific to raltegravir and independent of the direct-acting antiviral effect of the drug, since treatment with the DNA polymerase inhibitor phosphonoacetic acid did not induce these host-targeted effects. Taken together, these results indicate that raltegravir has profound and specific effects on the host transcription profile of herpesvirus-infected cells that may contribute to the overall antiviral activity of the drug and could provide therapeutic benefits in vivo. Furthermore, this study provides a framework for future efforts evaluating the host-targeted effects of anti-microbial compounds.
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PMID:Transcriptome profiling of alphaherpesvirus-infected cells treated with the HIV-integrase inhibitor raltegravir reveals profound and specific alterations in host transcription. 2991 4

Alphaherpesvirus-associated ocular infections in humans caused by human alphaherpesvirus 1 (HHV-1) remain challenging to treat due to the frequency of drug application required and the potential for the selection of drug-resistant viruses. Repurposing on-the-market drugs is a viable strategy to accelerate the pace of drug development. It has been reported that the human immunodeficiency virus (HIV) integrase inhibitor raltegravir inhibits HHV-1 replication by targeting the DNA polymerase accessory factor and limits terminase-mediated genome cleavage of human betaherpesvirus 5 (HHV-5). We have previously shown, both in vitro and in vivo, that raltegravir can also inhibit the replication of felid alphaherpesvirus 1 (FeHV-1), a common ocular pathogen of cats with a pathogenesis similar to that of HHV-1 ocular disease. In contrast to what was reported for HHV-1, we were unable to select for a raltegravir-resistant FeHV-1 strain in order to define any basis for drug action. A candidate-based approach to explore the mode of action of raltegravir against FeHV-1 showed that raltegravir did not impact FeHV-1 terminase function, as described for HHV-5. Instead, raltegravir inhibited DNA replication, similarly to HHV-1, but by targeting the initiation of viral DNA replication rather than elongation. In addition, we found that raltegravir specifically repressed late gene expression independently of DNA replication, and both activities are consistent with inhibition of ICP8. Taken together, these results suggest that raltegravir could be a valuable therapeutic agent against herpesviruses.IMPORTANCE The rise of drug-resistant herpesviruses is a longstanding concern, particularly among immunocompromised patients. Therefore, therapies targeting viral proteins other than the DNA polymerase that may be less likely to lead to drug-resistant viruses are urgently needed. Using FeHV-1, an alphaherpesvirus closely related to HHV-1 that similarly causes ocular herpes in its natural host, we found that the HIV integrase inhibitor raltegravir targets different stages of the virus life cycle beyond DNA replication and that it does so without developing drug resistance under the conditions tested. This shows that the drug could provide a viable strategy for the treatment of herpesvirus infections.
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PMID:The HIV Integrase Inhibitor Raltegravir Inhibits Felid Alphaherpesvirus 1 Replication by Targeting both DNA Replication and Late Gene Expression. 3004 87