Mechanism of action of antiviral drugs for CMV. In the CMV-infected cell, GCV and valganciclovir (VGCV) undergo phosphorylation by UL97 kinase (pUL97) and cellular kinases. CDV phosphorylation is independent of pUL97; cellular kinases add an additional phosphate. GCV, VGCV, and CDV compete with deoxynucleotide triphosphate (dNTP) for the binding site on pUL54 (CMV DNA polymerase [pol]). FOS does not require phosphorylation. Once inside the CMV-infected cell, FOS directly inhibits CMV DNA replication by binding to the pyrophosphate (ppi) site of pUL54. Alterations in the substrate binding or phosphate transfer sites of pUL97 confer UL97 resistance to GCV and VGCV. Alterations in the catalytic site or relative increases in the exonuclease activity of pUL54 confer UL54 resistance to GCV, VGCV, and CDV. Alterations of the ppi binding site of pUL54 confer UL54 resistance to FOS.