Mechanism of inhibition by acyclovir triphosphate. Potent inhibition of HSV-1 DNA polymerase was observed upon binding of the next deoxynucleoside 5′-triphosphate coded by the template subsequent to the incorporation of acyclovir monophosphate into the 3′-end of the primer. Studies indicated that potent, reversible inhibition by ACVTP and the next required deoxynucleoside 5′-triphosphate also occurred when poly(dC)-oligo(dG) or activated calf thymus DNA were used as the template-primer. Once incorporated, acyclovir irreversibly binds to viral DNA polymerase, effectively inactivating the enzyme. Acyclovir triphosphate is a potent inhibitor of all of the human herpes virus DNA polymerases studied. In all studies of valacyclovir, the half-life of acyclovir typically averages 2.5 to 3.3 hours in subjects with normal renal function. Acyclovir triphosphate is both an inhibitor of, and a substrate for, herpesvirus-specified DNA polymerase. All patients were treated within 24 hours after the onset of rash. This third mechanism of resistance involving herpes simplex virus DNA polymerase is due to the selection of mutants encoding an altered enzyme, which is resistant to inactivation by acyclovir triphosphate.
Clinical treatment resistance is associated with acyclovir-resistant HSV strains, but acyclovir-resistant strains were also isolated from treatment-naive subjects. This drug is phosphorylated in infected mammalian cells by the viral thymidine kinase to acyclovir monophosphate, which is itself further phosphorylated by host kinases to acyclovir triphosphate, a potent inhibitor of the viral DNA polymerase. Core study data were available for all such identified matched control subjects. LBV triphosphate inhibits the viral DNA polymerase competitively with dGTP. Previous antiviral studies on herpes viruses have focussed on developing nucleoside analogues that can inhibit viral polymerase and terminate the replicating viral DNA. 815 and Tyr 818, all of which are crucial to the proper functioning of the polymerase. Results of these studies will also guide the design of selective inhibitors of DNA POL with high specificity and potent activity in order to strengthen the therapeutic arsenal available today against the dangerous biological warfare agent represented by Herpes Simplex Virus. A number of new anti-viral drugs against HSV DNA polymerase are currently under research and development; these focus other domains of the polymerase than those targeted by the commercially available drugs 14.
Acyclovir Triphosphate Is a Suicide Inactivator of the Herpes Simplex Virus DNA Polymerase on ResearchGate, the professional network for scientists. These studies indicated that a reversible enzyme-ACVTP (Michaelis-type) complex is formed at the active site prior to inactivation. These data indicate that ACVTP functions as a suicide inactivator of the herpes simplex virus type 1 DNA polymerase, and is only a weak reversible inhibitor of DNA polymerase alpha. All rights reserved. However. acyclovir and AZT do not approach penicillin in their spectra of activity or degree of inhibition. This specifically inhibits herpesvirus DNA polymerase at the pyrophosphate binding sites and it also has anti-HIV activity. All the antiviral drugs now known were discovered by random search in the laboratory. A recent example of the success of this new rational approach has been the discovery of potent neuraminidase inhibitors of influenza viruses. Glycoprotein D is the most potent inducer of neutralizing antibodies and appears related to viral entry into a cell, and gB also is required for infectivity. Animal vectors for human HSV infections have not been described, and humans remain the sole reservoir for transmission to other humans. Not all people with first clinical episodes of symptomatic genital herpes actually have first episode primary or nonprimary infections: approximately 20 of such persons will have serologic evidence of HSV-2 at presentation, indicative of past asymptomatic acquisition of HSV-2 (62, 139). EBV DNA polymerase is susceptible to inhibition by acyclovir triphosphate and thus EBV is moderately susceptible to acyclovir in vitro.
A Retrospective, Case-control Study Of Acyclovir Resistance In Herpes Simplex Virus
Herpes simplex virus DNA polymerase (HSV pol) holoenzyme consists of a large catalytic (UL30 gene product) and a small auxiliary subunit (UL42 gene product) 2. The diphosphate derivative of (RS)-FPMPA (RS)-FPMPApp is a potent and selective inhibitor of HIV-1 reverse transcriptase but not of HSV-1 DNA polymerase or DNA polymerase alpha 8. Mechanism of inhibition by acyclovir triphosphate 13. Acyclovir triphosphate and Foscarnet, along with the closely related phosphonoacetic acid, did not affect exonuclease activity on single-stranded DNA. Table 1 lists the sequences of all primers and templates used in this study. Reardon JE, Spector T: Herpes simplex virus type 1 DNA polymerase. Mechanism of inhibition by acyclovir triphosphate.