Deoxyguanosine triphosphate

The active metabolite of acyclovir inhibits herpesvirus DNA replication in two ways. Acyclovir triphosphate acts as a competitive inhibitor for the incorporation of deoxyguanosine triphosphate (dGTP) into the viral DNA. In addition, acyclovir that is incorporated into viral DNA acts as a chain terminator because it lacks the 3 -hydroxy group necessary for further chain elongation. Viral DNA polymerase becomes irreversibly bound to an acyclovir-terminated DNA chain and is unavailable for further replicative activity. The effect of acyclovir on host cell DNA synthesis is much smaller than its effect on the viral enzyme. Concentrations of acyclovir significantly beyond the therapeutic range are required to inhibit host cell growth. 

Mechanism of Action Penciclovir triphosphate inhibits HSV polymerase competitively with deoxyguanosine triphosphate. Consequently, herpes viral DNA synthesis and, therefore, replication are selectively inhibited. Therapeutic Effect An antiviral compound that has inhibitory activity against herpes simplex virus types 1 (HSV-1)... 

Inhibits HSV-2 polymerase competitively with deoxyguanosine triphosphate, selectively inhibiting herpes viral DNA synthesis and replication... 

An example has been published (11) in which TIBO R82150 [126320-77-2] (6), an inhibitor of the HIV-1 RT, is noncompetitive with respect to one substrate, deoxyguanosine triphosphate (AirTP), yet uncompetitive with respect to the second, the template—primer complex poly(C) (dG)12 18. The IC50... 

The initial rate of reaction for the enzymatic cleavage of deoxyguanosine triphosphate was measured as a function of initial substrate concentration as follows (Kornberg et al., J.Biol.Chem., 233, 159, 1958) ... 

Ap, 13.6Ap, 13.8Q,p Butyl acetate 10.4o Butylbicyclophosphorothioate 3.2Bn Butyl butyrate 10.4o Butyl-deoxygalactonojirimycin 13.1a Butyldesmethylibogaine 3.3Aa Butylheptylpyrrolidine 3.4An Butylidene-tetrahydro-dihydroxy-isobenzofuranone 4. lAp Butylphenyl-deoxyguanosine-triphosphate 9.3Dn... 

Aciclovir is converted by thymidine kinase within viral cells to aciclovir triphosphate, which is then incorporated into viral DNA instead of the deoxyguanosine triphosphate required for DNA synthesis and replication. 

A mechanistic proposal, supported by the crystal structure of the enzyme with bound deoxyguanosine triphosphate, is outlined in Fig. 14 [66,67]. 

Acyclovir 4,19) is undoubtedly the most interesting of the known anti-viral drugs because of its.high therapeutic index. It is, for example, 3000 times more toxic to herpes simplex virus than to mammalian cells. Somewhat like amino-idoxuridine 4,14b), acyclovir is monophosphorylated by a virus-specified thymidine kinase and then converted to the triphosphoryl derivative which injures the virus by competing, against deoxyguanosine triphosphate, for the virus-specified DNA polymerase in the infected cells (Fyfe et al, 1978). This inhibition puts an end to all DNA synthesis in these cells. Its phosphorylation does not take place in healthy cells, which are thereby spared, and this accounts for most of the selectivity. For the rest the DNA polymerase of infected cells is more sensitive to acyclovir triphosphate than is the DNA polymerase of healthy mammalian cells which, in any case, receive very little of this product (Elion, 1980). 

DNA recognition has been achieved, for example by the sorption of DNA in PP [209] or by PP functionalized with a covalently linked oligonucleotide [208], Deoxyguanosine-triphosphate and 5 -phosphate modified deoxyguanosine oligonucleotide (an oligomer containing twenty monomer units) was immobilized in poly-thionine [222],... 

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