Drugs for cytomegalovirus (CMV) infection
The anti-human CMV drugs used currently target CMV replication via two distinct mechansims.
Ganciclovir (GCV; Cytovene) is a nucleoside analogue. It must be phosphorylated (to the nucleotide) by the viral protein kinase, pUL97 to confer anti-viral activity. Use of GCV as prophylaxis for CMV is limited by clinically significant myelosuppression. GCV is more commonly used to treat CMV retinitis, usually in patients who have suppressed immune systems (e.g. AIDS patients and solid organ transplant patients). It is also used to treat ocular ulcers caused by the herpes simplex virus.
Valganciclovir (Valcyte) is a GCV prodrug, that is generally used to prevent CMV reactivation or infection that may occur after a solid organ transplant. Like ganciclovir it causes significant myelosuppression.
Cidofovir (CDV), on the other hand is a nucleotide analogue, and does not need modification for activity. Cidofovir is only used to treat CMV retinitis in AIDS patients.
Foscarnet (FOS) inhibits pUL54 activity by binding to the enzyme's pyrophosphate binding site. It is used to treat CMV retinitis in AIDS patients and HSV infection in immunocompromised patients after failure to respond to other antiviral drugs.
Mutations in either pUL97 or pUL54 can result in resistance against these three drugs. Most cases of resistance to GCV are due to mutations in the UL97 gene, but mutations in the UL54 gene can also cause antiviral resistance. The problem of resistance to current drugs has been addressed by the development of compounds with an alternative mechanism to disrupt viral replication.
Viral terminase inhibitor
Letermovir (Prevymis) is the most recently approved anti-CMV medication (FDA approval granted in November 2017, and EMA marketing authorisation in January 2018). Letermovir inhibits the viral terminase complex (which consists of the CMV-encoded proteins pUL51, pUL56, and pUL89), which is a DNA packaging unit that is essential for DNA-containing viral capsid formation. By inhibiting terminase activity (by binding to pUL51 and/or pUL56), letermovir prevents CMV replication. This drug can be administerd orally or by i.v. infusion. It is approved as prophylaxis for CMV in allogeneic hematopoietic-cell transplantation patients who are receiving immunosuppressant therapy. It prevents CMV reactivation in these patients (see PMID: 29211658).