DNA polymerase inhibitors

To summarize, terminase inhibitors point the way toward a switch in strategy for developing HCMV inhibitors, with the aim of achieving a quality different from that of established DNA polymerase inhibitors. Intervention with viral DNA maturation arrests the replicative cycle at the DNA cleavage and packaging step, leading to an accumulation of empty procapsids and unprocessed concatemeric DNA. 

Terminase inhibition is an antiviral approach that may also be of consequence for other members of the herpesvirus group. In addition, since a similar DNA maturation process does not occur in higher cells, this principle offers the potential for high selectivity, in contrast to many of the viral DNA polymerase inhibitors, which also interact with cellular enzymes and hence can have severe side effects. 

Viral DNA polymerase is an important catalyst for the synthesis of viral nucleic acids. DNA polymerase inhibitors have already been encountered as antitumor agents. Ara-A (9.5, vidarabine) is a DNA polymerase inhibitor that has demonstrated activity against herpes simplex virus type I (HSV-1) infections, responsible for cold sores on... 

Gerona-Navarro and coworkers in 2004 have reported the synthesis and the evaluation of a series of new 2-azetidinones (Fig. 50), derived from phenylalanine [281], which were designed on the basis of the structure of the reported (3-lactam inhibitors [367] and the residues implicated in the active site of the HCMV protease [417]. These compounds have been evaluated against HCMV in human embryonic lung cells [418], and the results compared to those obtained for the reference compounds, which were the model (3-lactam la of Fig. 49, the viral DNA polymerase inhibitors DHPG (ganciclovir), and HPMPC (cidofovir). 

A separate positive control experiment was performed in which a known DNA polymerase inhibitor (3 pi of lamivudine at a concentration 3 mg/ml) was used instead of the tested inhibitor (3 pi). 

Kuramochi, K., Mizushina, Y., Nagata, S., Sugawara, F., Sakaguchi, K., Kobayashi, S. (2004). Structure-activity relationships of epolactaene analogs as DNA polymerase inhibitors. Bioorg. Med. Chem., 12, 1983-1989. 

Formulation, neurological (FIN) 156 RNA-directed DNA polymerase inhibitor (PO-RDNA-) 43... 

Huggins JW, Marteniz MJ, Zaucha GM, Jahrling PB, Smee D, Bray, M. 1998. The DNA Polymerase Inhibitor Cidofovir (HPMC, Vistide) is a Potential Antiviral Therapeutic Agent for the Treatment Of Monkeypox And Other Orthopox Virus Infections. Presented at the XII International Poxvirus Symposium, St Thomas, VI, June 6-10. 

Isol. from Phoma betae. Inhibitor of DNA polymerase. Inhibitor of seedling root growth. Needles. Mp 138-140.5°. [a] - 22.6 (c, 0.98 in EtOH). 

Pungitore CR, Ayub MJ, Garcia M, Borkowski EJ, Sosa ME, Ciuffo G, Giordano OS, Tonn CE (2004) Iridoids as allelochemicals and DNA polymerase inhibitors. J Nat Prod... 

Computational Approaches in Rational Design of DNA Polymerase Inhibitors... 

Mizushina Y, Kasai N, lijima H, Sugawara F, Yoshida H, Sakaguchi K (2005) Sulfo-quino-vosyl-acyl-glycerol (SQAG), a eukaryotic DNA polymerase inhibitor and anti-cancer agent. Curr Med Chem Anticancer Agents 5(6) 613-625... 

Andrei G, De Clereq E, Snoeck R (2009) Viral DNA polymerase inhibitors. In Raney KD, Gotte M, Cameron CE (eds) Viral genome replieation. Springer, New York, p 481-526... 

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