The antiviral activity of a guanosine derivative is tested by examining cells infected with different viruses for characteristic abnormal changes in cell morphology due to the viruses. These changes are known as the cytopathic effect (CPE). In the presence of significant antiviral activity, CPE will be inhibited. The following results are obtained from the study: A difference in which of the following best explains the variation in susceptibility of the various viruses to this specific antiviral agent?

Question

The antiviral activity of a guanosine derivative is tested by examining cells infected with different viruses for characteristic abnormal changes in cell morphology due to the viruses.  These changes are known as the cytopathic effect (CPE).  In the presence of significant antiviral activity, CPE will be inhibited.  The following results are obtained from the study:  A difference in which of the following best explains the variation in susceptibility of the various viruses to this specific antiviral agent?

Quizplus · Accepted Answer

11ec160b_3bee_cdbd_9249_5f48ddce0875_MD0001_00 The drug described in this study demonstrates significant antiviral activity (cytopathic effect) against herpes simplex virus type 1 (HSV 1), HSV 2, and varicella zoster virus (VZV) but has weak activity against Epstein-Barr virus (EBV) and cytomegalovirus (CMV). This agent is most likely acyclovir, a guanosine analog. Once acyclovir enters the HSV-infected host cell, it is phosphorylated to acyclovir monophosphate, principally via a virally-encoded thymidine kinase (TK). This is the rate-limiting step in acyclovir activation. Acyclovir monophosphate is then phosphorylated by cellular enzymes into the active triphosphate form, which impairs viral DNA polymerase-mediated replication of HSV. EBV and CMV do not produce the same TK as HSV and VZV. As a result, EBV- or CMV-infected cells cannot easily convert acyclovir into its pharmacologically active form. At very high intracellular concentrations of acyclovir, some of the drug appears to be activated by unidentified cellular phosphorylating enzymes, which may explain the partial susceptibility of EBV and CMV to higher acyclovir doses. The partial activity of acyclovir against CMV may also be mediated by inhibited synthesis of a virus-specific polypeptide. (Choices A, B, and E) Mutations in viral DNA polymerase can lead to acyclovir resistance, but differences in TK are the best explanation for the observed results. Drug degradation rate and viral protease activity are not responsible for differences in viral susceptibility to acyclovir. (Choice D) TK is an enzyme produced in infected cells, but it is not present in the capsid. Educational objective: Monophosphorylation of acyclovir by a viral thymidine kinase is the first (and rate-limiting) step in conversion of acyclovir to its active triphosphate form. Acyclovir and related drugs (eg, famciclovir, valaciclovir) are more effective against herpes simplex virus and varicella zoster virus than cytomegalovirus and Epstein-Barr virus.

The Antiviral Activity of a Guanosine Derivative Is Tested by Examining