Mechanism of DNA synthesis inhibition by acyclovir and the new drugs. a, HSV DNA synthesis. The helicase-primase complex, consisting of viral proteins UL5, -8 and -52, unwinds HSV DNA at the replication fork and primes both lagging-strand (wavy green lines) and leading-strand (not shown) DNA synthesis. The single-stranded DNA binding protein, ICP8, binds to single-stranded template DNA (straight blue lines). HSV DNA polymerase and its accessory protein, UL42, promote leading- and lagging-strand DNA synthesis (wavy blue lines). The arrows indicate the direction of movement of the DNA replication proteins. b, New drugs target the helicase-primase complex. The TZP/Us (amino-thiazolylphenyl-containing compounds and thiazole urea derivatives; red band) enhance binding of the UL5 and UL52 subunits of the helicase-primase complex to both leading- and lagging-strand DNA resulting in inhibition of helicase activity, primase activity and viral DNA synthesis. c, Acyclovir. Acyclovir triphosphate (orange wedge) binds to HSV DNA polymerase, inhibiting polymerase activity and synthesis of both leading and lagging DNA strands.

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