Dr. Stahelin Herpes Antivirals

Question 1

Acyclovir

Answer 1

• Acyclic guanosine derivative that lacks a 3’ hydroxyl group (cannot form phosphodiester bond) and selectively accumulates in infected cells results in infected cells.
• requires 3 phosphorylation events. 1st phosphorylation done by viral thymidine and last 2 done by cellular kinases
• a competitive inhibitor of viral DNA polymerase. Competes with dGTP (competition occurs at lower concentrations for viral DNA polymerase than host DNA polymerase). DNA polymerase becomes bound to the template irreversible and acyclovir is incorporated in the DNA and acts as a chain terminator.

Question 2

SOA of acyclovir

Answer 2

active against HSV-1, HSV-2, and VZV

Question 3

Resistance to acyclovir

Answer 3

mutations in viral thymidine kinase or mutations in viral DNA polymerase. Resistance emerges more frequently in immunocompromised people

Question 4

Valacyclovir

Answer 4

• L-valyl ester of acyclovir. Rapidly converted to acyclovir by esterases in the intestine and liver
• transported into intestinal amino acid transported
• same MOA, SOA, and resistance as acyclovir

Question 5

Penciclovir and Famciclovir

Answer 5

• Famciclovir is a prodrug of penciclovir (lacks intrinsic antiviral activity). Famciclovir is converted to penciclovir by first-pass metabolism in the intestine and liver. Conversion during first-pass metabolism is converted by esterase, esterase, and oxidase.
• MOA: activated by viral and cellular kinases. Competitive inhibitor of viral DNA polymerase. Does NOT cause immediate chain termination (allows short-chain elimination).

Question 6

Penciclovir SOA

Answer 6

HSV-1, HSV-2, and VZV

Question 7

Penciclovir vs Acyclovir

Answer 7

• penciclovir has a higher affinity for HSV TK than acyclovir (levels of penciclovir triphosphate in infected cells are much higher than the levels of acyclovir triphosphate)
• penciclovir triphosphate is more stable than acyclovir triphosphate in HSV-infected cells
• HSV DNA polymerase have higher affinity for acyclovir than penciclovir
• viral kinase mutants confer cross-resistance to penciclovir and acyclovir

Question 8

Ganciclovir

Answer 8

• structurally similar to penciclovir.
• Severe dose-limiting toxicity: bone marrow suppression
• poor bioavailability
• MOA: competitive inhibitor of DNA polymerase. Does NOT cause immediate chain termination (allows for short-chain elimination)
• SOA: CMV
• Resistance: mutations in CMV kinase (UL97 gene) or CMV DNA polymerase (UL54). Mutations in kinase are not cross-resistance to cidofovir or foscarnet

Question 9

Valganciclovir

Answer 9

• monovalyl ester of ganciclovir (pro-drug) to increase the bioavailability
• rapidly hydrolyzed to ganciclovir by esterases in the intestine and liver
• MOA: competitive inhibitor of viral DNA polymerase. Does not cause immediate chain termination (allows for short-chain elimination)
• SOA: CMV
• Resistance: mutations in CMV kinase (UL97 gene) or CMV DNA polymerase (UL54). Mutations in kinase are not cross-resistant to cidofovir or foscarnet

Question 10

Foscarnet

Answer 10

• inorganic pyrophosphate compound (phosphonoformic acid)
• does not require phosphorylation for activity
• MOA: inhibits viral DNA polymerase, RNA polymerase, and HIV RT. Blocks pyrophosphate binding site of the viral DNA polymerase and inhibits cleavage of pyrophosphate from dNTPs.
• Carboxyl overlaps with the binding site of beta-phosphate. Phosphonates occupies position of gamma-phosphate and traps polymerase in closed formation. DNA is unable to translocate.

Question 11

Foscarnet SOA and resistance

Answer 11

• CMV (used to treat CMV retinitis and works synergistically with ganciclovir against CMV)
• Mutations in DNA polymerase or HIV RT. Resistant CMV isolates are cross-resistant to ganciclovir. Usually still effective against ganciclovir and cidofovir resistant CMV.

Question 12

Cidofovir

Answer 12

• acyclic nucleoside phosphonate analog of cytosine
• phosphonate cannot be cleaved by cellular esterases making it catabolically stable
• phosphorylated (2x) by cellular kinases, does not require activation by viral kinases
• MOA: competitive inhibitor of viral DNA polymerase and chain terminator. Chain termination by CMV polymerase requires two consecutive incorporations
• SOA: CMV, HSV-1, HSV-2, VZV, EBV, HHV-6, HHV-8, adenovirus, poxvirus, polyomavirus, and human papillomavirus.

Question 13

Letermovir

Answer 13

• MOA: herpesvirus DNA replication is through a rolling circle mechanism and produces concatemers Individual genomes must be cut out by terminase complex- which is made up of pUL56, 89, 51. Letermovir inhibits terminase complex by binding to pUL56 and preventing cleaving and packaging of viral DNA.
• SOA: CMV
• Resistance: no cross-resistance to other CMV drugs