Acyclоvir is аn аntivirаl agent primarily used tо treat infectiоns caused by herpesviruses, including herpes simplex virus (HSV) and varicella-zoster virus (VZV). Its mechanism of action is based on selective inhibition of viral DNA replication. Acyclovir is a guanine analog that lacks a 3'-hydroxyl group, which is essential for DNA chain elongation. When acyclovir enters the infected host cell, it is selectively phosphorylated by the viral enzyme thymidine kinase to its active monophosphate form. Cellular kinases then convert the monophosphate form into the active triphosphate form, acyclovir triphosphate. Acyclovir triphosphate competes with the natural nucleotide deoxyguanosine triphosphate (dGTP) for incorporation into the growing viral DNA chain by the viral DNA polymerase. Once incorporated, acyclovir triphosphate terminates DNA chain elongation due to the absence of the 3'-hydroxyl group required for adding the next nucleotide. This leads to premature termination of viral DNA synthesis. Because acyclovir is selectively activated by the viral thymidine kinase and preferentially inhibits viral DNA polymerase over host DNA polymerase, its cytotoxicity to uninfected cells is minimal. Acyclovir-resistant strains of HSV and VZV have emerged, primarily due to mutations in the viral thymidine kinase or viral DNA polymerase, which reduce the efficacy of acyclovir. These mutations can either prevent the activation of acyclovir or reduce its incorporation into viral DNA, limiting its therapeutic effects. Despite this, acyclovir remains a cornerstone of antiviral therapy, particularly for herpes simplex encephalitis and neonatal herpes, where early intervention can prevent severe neurological damage. Acyclovir functions as a chain terminator when incorporated into viral DNA because:
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