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)

Acyclovir (Zovirax) is a qualified success as an effective and nontoxic antiviral chemotherapeutic agent and at present is approved for the treatment of initial genital herpes and limited life-threatening cutaneous herpes simplex viral infections in the immunocompromised host. Its efficacy in Epstein-Barr, varicella-zoster, and cytomegalorvirus infections appears less promising. According to one controlled study, its efficacy in the treatment of herpes labialis (HSV-1) infections has been disappointing. The highly selective action of acyclovir against viral DNA polymerase and its inhibition of viral DNA chain elongation result in a low incidence of human (host cell) toxicity, as manifested by local irritation at injection sites and a modest incidence of adverse renal effects, which can be reduced by judicious drug use. Newer antiviral agents now under development hold substantial promise for the future of antiviral chemotherapy.
 ...
PMID:Acyclovir and herpesvirus infections. A review of the literature. 632 78

5-Isopropyl-2'-deoxyuridine is the active ingredient of Hevizos ointment, a commercially available drug in Hungary, applied on the local treatment of patient with herpes labialis, zoster and progenitalis. The 5'-triphosphate derivative of the compound was incorporated by a DNA polymerase enzyme into a synthetic DNA of poly(dA-dT) type in order to study possible alterations in the structure and bioorganic functions of the DNA, in comparison with unmodified poly(dA-dT). Alterations observed by spectroscopic, electron microscopic and biochemical methods refer to the formation of stable hairpins protruding from the DNA duplex, which may be responsible for the impairment of the integrity of the DNA structure. This, in turn, may negatively influence normal biochemical functions of a DNA.
 ...
PMID:[Incorporation of the antiherpetic 5-isopropyl-2'-deoxyuridine into a synthetic DNA and the consequence of incorporation on structure and functions of the DNA]. 837 36

The quiet pandemic of herpes simplex virus (HSV) infection has plagued humanity since ancient times, causing mucocutaneous infection, such as herpes labialis and herpes genitalis. Disease symptoms often interfere with everyday activities and occasionally HSV infections are the cause of life-threatening or sight-impairing disease, especially in neonates and the immunocompromised patient population. After primary or initial infection the virus persists for life in a latent form in neurons of the host, periodically reactivating and often resulting in significant psychosocial distress for the patient. Currently, no cure is available. In the mid-1950s the first antiviral, idoxuridine, was developed for topical treatment of herpes disease and, in 1978, vidarabine was licensed for systemic use to treat HSV encephalitis. Acyclovir (Zovirax), a potent, specific and tolerable nucleosidic inhibitor of the herpes DNA polymerase, was a milestone in the development of antiviral drugs in the late 1970s. In the mid-1990s, when acyclovir became a generic drug, valacyclovir (Valtrex) and famciclovir (Famvir), prodrugs of the gold standard and penciclovir (Denavir), Vectavir), a close analogue, were launched. Though numerous approaches and strategies were tested and considerable effort was expended in the search of the next generation of an antiherpetic therapy, it proved difficult to outperform acyclovir. Notable in this regard was the award of a Nobel Prize in 1988 for the elucidation of mechanistic principles which resulted in the development of new drugs such as acyclovir. Vaccines, interleukins, interferons, therapeutic proteins, antibodies, immunomodulators and small-molecule drugs with specific or nonspecific modes of action lacked either efficacy or the required safety profile to replace the nucleosidic drugs acyclovir, valacyclovir, penciclovir and famciclovir as the first choice of treatment. Recently though, new inhibitors of the HSV helicase-primase with potent in vitro antiherpes activity, novel mechanisms of action, low resistance rates and superior efficacy against HSV in animal models have been discovered. This review summarises the current therapeutic options, discusses the potential of preclinical or investigational drugs and provides an up-to-date interpretation of the challenge to establish novel treatments for herpes simplex disease.
 ...
PMID:Novel agents and strategies to treat herpes simplex virus infections. 1255 12

(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