Adenovirus inhibition

Johnson TW, Wu YX, Herdeg C, et al, Stent-based delivery of tissue inhibitor of metalloproteinase-3 adenovirus inhibits neointimal formation in porcine coronary arteries. Arterioscler Thromb Vase Biol 2005 25(4) 754-759. 

Nasimuzzaman M, Kuroda M, Dohno S, Yamamoto T, Iwatsuki K, Matsuzaki S, Mohammad R, Kumita W, Mizuguchi H, Hayakawa T, Nakamura H, Taguchi T, Wakiguchi H, Imai S (2005) Eradication of Epstein-Barr virus episome and associated inhibition of infected tumor cell growth by adenovirus vector-mediated transduction of dominant-negative EBNAl. Mol Ther 11 578-590... 

Zhu Y, CuUen JM, Aldrich CE, SaputelU J, MiUer D, Seeger C, Mason WS, JUbert AR (2004) Adenovirus-based gene therapy during clevudine treatment of woodchucks chronically infected with woodchuck hepatitis virus. Virology 327 26 0 zu Putlitz J, Wieland S, Blum HE, Wands JR (1998) Antisense RNA complementary to hepatitis B virus specifically inhibits viral replication. Gastroenterology 115 702-713... 

The structure/activity relationships for the methisazone, 3a, derivatives against adenoviruses and poxviruses have been shown to be similar [78]. Pearson and Zimmerman [79] demonstrated that all three types of polioviruses are inhibited by 2-acetylpyridine JV-dibutylthiosemicarbazone, which is similar to 3a, by blocking viral RNA synthesis. A 3-substituted triazinoindole derivative of isatin was effective against several strains of rhinovirus in tissue culture the mechanism of action is unknown [80]. 

The answer is b. (Hardman, p 1203.) Trifluridine inhibits viral activity in HSV types 1 and 2, CMV, vaccinia, and perhaps adenovirus. It acts as a viral DNA synthesis inhibitor by irreversibly blocking thymidylate synthetase. Trifluridine triphosphate is a competitive inhibitor of thymidine triphosphate accumulation into DNA It is used in the treatment of primary keratoconjunctivitis and recurrent epithelial keratitis caused by HSV 1 and 2. 

Li+ has significant inhibitory effects upon DNA viruses, in particular HSV which has been studied in depth. It was originally shown that Li+ inhibits viral replication in a dose-dependent, reversible manner in HSV-infected baby hamster kidney cells [240], and this has been found to be due to a Li+-induced decrease in the synthesis of viral DNA [241]. It is now well established that Li+ inhibits DNA synthesis in HSV types 1 and 2 and in several other DNA viruses, including measles, vaccinia, adenovirus, poxvirus, pseudorabies virus, Epstein-Barr virus, and the bovine, equine, and canine HV s [241]. Interestingly, Li+ has no effect on the replication of RNA viruses, such as influenza or encephalomyo-carditis virus. 

Pharmacology A fluorinated pyrimidine nucleoside with in vitro and in vivo activity against herpes simplex virus types 1 and 2, and vaccinia virus. Some strains of adenovirus are also inhibited in vitro. Its antiviral mechanism of action is not completely known. 

Cidofovir (Vistide) is an acyclic phosphonate cytosine analogue with activity against herpesviruses including CMV, HSV-1, HSV-2, EBV, and VZV. It also inhibits adenoviruses, papillomaviruses, polyomaviruses, and poxviruses. Activation of cidofovir requires metabolism to a diphosphate by host cellular enzymes. Because this activation does not depend upon viral enzymes, similar levels of cidofovir diphosphate are seen in infected and uninfected cells. Cidofovir diphosphate competes with deoxycytidine triphosphate (dCTP) for access to viral... 

Trifluridine (Viroptic) is a fluorinated pyrimidine nucleoside that has in vitro activity against HSV-1 and HSV-2, vaccinia, and to a lesser extent, some adenoviruses. Activation of trifluridine requires its conversion to the 5 monophosphate form by cellular enzymes. Trifluridine monophosphate inhibits the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) by thymidylate synthetase. In addition, it competes with deoxythymidine triphosphate (dTTP) for incorporation by both viral and cellular DNA polymerases. Trifluridine-resistant mutants have been found to have alterations in thymidylate synthetase specificity. 

DNA viruses that can trigger tumors are found in the classes of the polyomaviruses, the adenoviruses and the papUloma viruses. The polyoma viruses with the SV40 virus as a well studied representative, adenoma virus and human papUloma virus (HPV) are associated with formation of tumors in humans and have genes coding for proteins with the properties of oncoproteins. The oncoproteins of aU three viruses interfere with the pRb function by Ufting its inhibition of transcription factor E2F. It is assumed that the tumor-promoting activity of the proteins is due, in particular, to this property. 

George, S.J., C.T. Lloyd, G.D. Angehni,A.C. Newby, and A.H. Baker, Inhibition of late vein graft neointima formation in human and porcine models by adenovirus-mediated overexpression of tissue inhibitor of metalloproteinase-3. Circulation, 2000.101(3) 296-304. 

A very different approach is to use wild type adenovirus to treat tumors that have a mutated p53 gene. This strategy is based on the premise that wild-type p53 inhibits adenoviral replication. Hence tumors with an inactive form of p53 will allow the virus to replicate and lyse cancerous cells [23]. 

Isoborneol has been found to be an interesting compound for inhibiting HSV life cycle, on the basis of the specificity of the inhibition of the glycosilation of viral polyptides [137]. Also linalool exhibited the strongest activity against adenoviruses however, carvone, cineole, -caryophyllene, farnesol, fenchone, geraniol, -myrcene and a-thujone did not exhibit activity [135]. 

Trifluridine (trifluorothymidine) is a fluorinated pyrimidine nucleoside that inhibits viral DNA synthesis in HSV-1, HSV-2, CMV, vaccinia, and some adenoviruses. It is phosphorylated intracellularly by host cell enzymes, and then competes with thymidine triphosphate for incorporation by the viral DNA polymerase (Figure 49-3). Incorporation of trifluridine triphosphate into both viral and host DNA prevents its systemic use. Application of a 1% solution is effective in treating keratoconjunctivitis and recurrent epithelial keratitis due to HSV-1 or HSV-2. Cutaneous application of trifluridine solution, alone or in combination with interferon alfo, has been used successfully in the treatment of acyclovir-resistant HSV infections. 

Czubayko, F., Downing, S.G., Hsieh, S.S., Goldstein, D.J., Lu, P.Y., Trapnell, B.C. and Wellstein, A. (1997a) Adenovirus-mediated transduction of ribozymes abrogates HER-2/neu and pleiotrophin expression and inhibits tumor cell proliferation. Gene Then, 4, 943-949. 

Perlman, H., Sata, M., Krasinski, K., Dorai, T., Buttyan, R. and Walsh, K. (2000) Adenovirus-encoded hammerhead ribozyme to Bcl-2 inhibits neointimal hyperplasia and induces vascular smooth muscle cell apoptosis. Cardiovasc. Res., 45, 570-578. 

Suzuki, T., Anderegg, B., Ohkawa, T., Irie, A., Engebraaten, O., Halks-Miller, M. etal. (2000) Adenovirus-mediated ribozyme targeting of HER-2/neu inhibits in vivo growth of breast cancer cells. Gene Ther., 7,241-248. 

Cidofovir is a cytosine nucleotide analog with in vitro activity against CMV, HSV-1, HSV-2, VZV, EBV, HHV-6, HHV-8, adenovirus, poxviruses, polyomaviruses, and human papillomavirus. In contrast to ganciclovir, phosphorylation of cidofovir to the active diphosphate is independent of viral enzymes. After phosphorylation, cidofovir acts both as a potent inhibitor of and as an alternative substrate for viral DNA polymerase, competitively inhibiting DNA synthesis and becoming incorporated into the viral DNA chain. Isolates with resistance to cidofovir have been selected in vitro these isolates tend to be cross-resistant with ganciclovir but retain susceptibility to foscamet. Clinically significant resistance to cidofovir has not been reported to date. 

Qin, L. H., Ding, Y. Z., Pahud, D. R., Robson, N. D., Shaked, A. and Bromberg, J. S. (1997). Adenovirus-mediated gene transfer of viral interleukin-10 inhibits the immune response to both alloantigen and adenoviral antigen. Hum. Gene Ther. 8, 1365-1374. 

Harell RL, Rajanayagam S, Doanes AM, et al. Inhibition of vascular smooth muscle cell proliferation and neointimal accumulation by adenovirus-mediated gene transfer of cytosine deaminase, Circulation 1997 96 621-627. 

Dorner, A., Xiong, D., Couch, K., Yajima, T., and Knowlton, K.U. (2004). Alternatively spliced soluble coxsackie-adenovirus receptors inhibit coxsackievirus infection. J Biol Chem 279, 18497-18503. 

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