Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022568 (keratitis)
 5,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

8-Hydroxyquinoline and several of its derivatives inactivate the transforming ability of Rous sarcoma virus and inhibit its ribonucleic acid-dependent deoxyribonucleic acid polymerase activity. The copper complex of these metal-binding ligands is as active as the free ligand. The activity of the 8-hydroxyquinolines is approximately 50-fold more effective than another group of metal-binding compounds that we have tested, the thiosemicarbazones. In contrast to the potency of the 8-hydroxyquinolines to inactivate Rous sarcoma virus, no intracellular inhibition of transformation could be demonstrated at a concentration that did not affect the growth and appearance of the cells. Cellular deoxyribonucleic acid synthesis was inhibited to a greater extent than was ribonucleic acid or protein synthesis. The phenomenon of "concentration quenching" was observed with high concentrations of drug, causing less inhibition of deoxyribonucleic acid synthesis than was observed with lower concentrations. Herpes simplex virus type 1 was inactivated also by the 8-hydroxyquinolines and their copper complexes. No intracellular inhibition of plaque formation was observed. Treatment with 8-hydroxyquinoline sulfate had no effect on the resolution of herpetic keratitis in rabbits. Some 8-hydroxyquinolines bind to deoxyribonucleic acid in the presence of copper, a phenomenon that may be important in their antiviral activity.
 ...
PMID:Hydroxyquinolines inhibit ribonucleic acid-dependent deoxyribonucleic acid polymerase and inactivate Rous sarcoma virus and herpes simplex virus. 18 49

In the rabbit 5% phosphonoacetic acid ointment suppressed herpetic keratitis as well as 0-5% idoxuridine ointment. After 5 days of treatment quantitative virus titres showed that phosphonoacetic acid was superior to idoxuridine in the inhibition of herpes virus replication. Phosphonoacetic acid was found to be nontoxic to the eye in both clinical and histopathological studies. Recent reports suggest that the mechanism of action of phosphonoacetic acid appears to be the blocking of the virus DNA polymerase, which is essential for the synthesis of herpes virus DNA.
 ...
PMID:Effect of phosphonoacetic acid in the treatment of experimental herpes simplex keratitis. 19 32

Idoxuridine which was first used in 1960 (Kaufman et al., 1962), has been for many years the only antiviral agent available in the treatment of herpetic keratitis. It is however no more successful than is mechanical removal of diseased epithelium (Patterson & Jones, 1967), and furthermore it may give rise to serious toxic side effects. The search for an alternative medication is therefore a pressing one. Trifluorothymidine (F3T) has, in recent years, been shown to be more effective than IDU and to be free from significant toxicity. Both of these drugs are pyrimidine nucleosides. Adenine Arabinoside or Arabinoside-A (Ara-A) is, by contrast, a purine nucleoside. It is thought to exert its antiviral effect by blocking DNA polymerase and ribonucleotide reductase.
 ...
PMID:Treatment of herpetic keratitis. 41 44

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.
 ...
PMID:Effect of trisodium phosphonoformate and idoxuridine on experimental herpes simplex keratitis in immunized and non-immunized rabbits. 624 66

The severity of herpetic keratitis induced by 9-(2-hydroxyethoxymethyl) guanine-resistant strains of herpes simplex virus was significantly reduced by cotherapy with 9-beta-D-arabinofuranosyladenine (ara-A) and 2-deoxycoformycin. Therapy with 5-trifluoromethyl-2'-deoxyuridine (F3TdR) significantly reduced the severity of keratitis induced by an acyclovir-resistant strain with a defective DNA polymerase. Therapy with 3 percent acyclovir ointment slightly reduced the number of herpetic lesions produced by either deoxypyrimidine kinase or DNA polymerase defective viruses, despite these viruses being 100 to 1000 times more resistant to acyclovir than the wildtype strain. Therapy with 3 percent ara-A ointment alone significantly reduced the severity of lesions produced by the wildtype herpes strain. Therapy with ara-A alone did not reduce the severity of disease induced by any of the acyclovir-resistant mutants. The sensitivity of the wildtype and mutant viruses to nucleoside analogs was confirmed by yield-reduction assays conducted with Vero cells. These studies indicate that cotherapy with ara-A and an adenosine deaminase inhibitor was a reasonable alternative therapy for keratitis due to mutants resistant to therapy with nucleoside analogs which require the virus-specified deoxypyrimidine kinase or DNA polymerase, while ara-A alone was not an effective alternative.
 ...
PMID:Chemotherapy of herpetic keratitis induced by acyclovir-resistant strains of herpes simplex virus type 1. 628 20

We have purified and characterized Pseudorabies virus (PRV) DNA polymerase from infected TK- mouse cells. PRV DNA polymerase has a 3'- > 5' exonuclease activity; it is stimulated by ionic strength, requires magnesium for optimal activity and it is more sensitive to aphidicolin than eukaryotic and HSV-1 replicative DNA polymerases. Aphidicolin inhibits in vitro PRV DNA polymerase competitively with respect to dCTP with a Ki of 0.06 microM and completely blocks viral growth in vivo at 4.4 microM. The high sensitivity to aphidicolin of animal herpesvirus DNA polymerases might allow a topical use of this drug in the treatment of animal herpesvirus keratitis and stomatitis.
 ...
PMID:Aphidicolin inhibits in vitro the activity of pseudorabies virus (PRV) DNA polymerase and in vivo the viral proliferation. 777 34

(E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU, Brivudin, Zostex, Zerpex, Zonavir), now more than 20 years after its discovery, still stands out as a highly potent and selective inhibitor of herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV) infections. It has been used in the topical treatment of herpetic keratitis and recurrent herpes labialis and the systemic (oral) treatment of herpes zoster (zona, shingles). The high selectivity of BVDU towards HSV-1 and VZV depends primarily on a specific phosphorylation of BVDU to its 5'-diphosphate (DP) by the virus-encoded thymidine kinase (TK). After further phosphorylation (by cellular enzymes), to the 5'-triphosphate (TP), the compound interferes as a competitive inhibitor/alternate substrate with the viral DNA polymerase. The specific phosphorylation by the HSV- and VZV-induced TK also explains the marked cytostatic activity of BVDU against tumor cells that have been transduced by the viral TK genes. This finding offers considerable potential in a combined gene therapy/chemotherapy approach for cancer. To the extent that BVDU or its analogues (i.e., BVaraU) are degraded (by thymidine phosphorylase) to (E)-5-(2-bromovinyl)uracil (BVU), they may potentiate the anticancer potency, as well as toxicity, of 5-fluorouracil. This ensues from the direct inactivating effect of BVU on dihydropyrimidine dehydrogenase, the enzyme that initiates the degradative pathway of 5-fluorouracil. The prime determinant in the unique behavior of BVDU is its (E)-5-(2-bromovinyl) substituent. Numerous BVDU analogues have been described that, when equipped with this particular pharmacophore, demonstrate an activity spectrum characteristic of BVDU, including selective anti-VZV activity.
 ...
PMID:(E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU). 1538 33

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.
...
PMID:The processivity factor complex of feline herpes virus-1 is a new drug target. 2554 73