Acyclovir: discovery, mechanism of action, and selectivity

Area of Science:

• Virology
• Molecular Biology
• Pharmacology

Background:

• Acyclovir is a crucial antiviral drug effective against herpesviruses.
• Understanding its mechanism of action is key to developing new antiviral therapies.

Purpose of the Study:

• To elucidate the mechanisms underlying acyclovir's selective activity against herpes simplex virus (HSV) and varicella-zoster virus (VZV).
• To highlight acyclovir's impact on antiviral chemotherapy and its relevance to emerging viral diseases.

Main Methods:

• The study summarizes known mechanisms of acyclovir's action, including viral thymidine kinase (TK) activation.
• It details the differential sensitivity and inactivation of viral DNA polymerase by acyclovir triphosphate (ACV-TP).
• Incorporation of acyclovir monophosphate (ACV-MP) leading to DNA chain termination is also discussed.

Main Results:

• Acyclovir is selectively activated by HSV/VZV-specified TK.
• Viral DNA polymerase is significantly more sensitive to ACV-TP than cellular polymerases.
• ACV-TP inactivates viral DNA polymerase but not cellular ones, and ACV-MP causes chain termination of viral DNA.

Conclusions:

• Acyclovir demonstrates remarkable selectivity, inhibiting viral DNA replication at sub-toxic concentrations.
• Its mechanism provides a paradigm for developing potent and selective antiviral agents.
• Acyclovir's success revitalized antiviral chemotherapy, offering a foundation for tackling diseases like AIDS.