ID 2 Final: Harrold CMV (p22-24)

termination, flexible

Ganciclovir

-gets converted to its triphosphate nucleotide, is incorporated into CMV

DNA by the enzyme CMV DNA polymerase, and causes chain ___ due to the ___ nature of the 3'-OH group

affinity, bioactivation

Why is ganciclovir selectively toxic to CMV?

-The selectivity is the result of a higher ___ of ganciclovir for CMV DNA polymerase as compared to human DNA polymerase

-Additionally, ganciclovir has been shown to have an increased ____ (conversion to the triphosphate) in infected cells as compared to uninfected cells.

phosphorylation, DNA polymerase

Ganciclovir-2 Mechanisms of Resistance

1. Decreased ___ to active triphophate via viral kinases

2. Mutations in viral __ ___ that alter its binding

bone marrow suppression

What is the major toxicity seen with ganciclovir?

Valganciclovir

What is the oral prodrug of ganciclovir?

bioavailable

Valganciclovir

-conceptually the same as valacyclovir

-10x more __ than ganciclovir

diphosphate

Cidofovir already has a phosphate; and therefore only needs to be phosphorylated two times to form its active metabolite, cidofovir ____

resistance, selectivity

Cidofovir MOA

-since the viral specific enzymes used by ganciclovir are not required, this drug can overcome __ to ganciclovir

-disadvantage = decreased ___

chain termination

Cidofovir MOA

-cidofovir diphosphate (remember this is really a triphosphate), selectively inhibits viral DNA synthesis to cause immediate __ __

longer

Compared to ganciclovir and foscarnet, Cidofovir has a ___ duration of action and can be given weekly or every 2 weeks

nephrotoxicity

What is its most serious adverse effect of Cidofovir?

probenecid

The most serious adverse effect of cidofovir is nephrotoxicity. This adverse effect can

be minimized by using cidofovir in combination with ____, which blocks the active

tubular secretion of cidofovir

pyrophosphate

What naturally occuring compound does Foscarnet mimic?

PFA

Foscarnet

-also known as phosphonoformic acid or __

pyrophosphate pocket

Foscarnet MOA

-binds to the ___ ___ of virus-specific DNA-polymerases and reverse transcriptases

human

Foscarnet is selective because it binds to viral specific DNA polymerases and reverse

transcriptase at concentrations that do not affect ___ cellular polymerases.

binding site

During the addition of a nucleotide to a growing DNA chain, a triphosphate is required Once the new nucleotide is added, pyrophosphate momentarily occupies what is known as the pyrophosphate ___ ___

sterically prevent

Normally, the pyrophosphate leaves and is hydrolyzed. Foscarnet, due to its ability to mimic pyrophosphate can bind to this same site, ____ ___ the next nucleotide from binding, and inhibit the CMV DNA polymerase.

prodrug

Foscarnet is different from other antimetabolites because it is NOT a ___ (so does not require activation)

IV

Foscarnet is used ___ because it is highly water soluble; It can easily dissolve, but cannot cross the GI membrane.

nephrotoxicity

What is the most serious side effect Foscarnet?