Week 16: Medicinal Chemistry

What structural class are most HSV antivirals?

acyclic nucleosides

What is the target of HSV nucleoside antivirals?

viral DNA polymerase (not host)

How are nucleoside antivirals activated?

phosphorylation → mono → di → triphosphate (active form)

What enzyme is unique for HSV activation?

viral kinase performs initial phosphorylation (rate-limiting)

Why not directly use acyclovir triphosphate since it is the active drug?

highly charged → poor membrane permeability → poor oral absorption, distribution, and rapid clearance (cannot effectively enter cells)

Why is acyclovir a chain terminator?

lacks 3′-OH → cannot extend DNA chain

What is the major limitation of acyclovir?

poor oral bioavailability (10-20%)

How was acyclovir improved?

converted to prodrug (valacyclovir)

How does valacyclovir improve pharmacokinetics?

↑ bioavailability (~55%), ↑ Cmax

How is valacyclovir converted to acyclovir?

hydrolyzed by carboxypeptidase

How is acyclovir eliminated?

~90% excreted unchanged in urine

What is the difference between ganciclovir and valganciclovir?

Ganciclovir = IV only; Valganciclovir = oral prodrug

Why is ganciclovir poorly absorbed?

high polarity (multiple OH groups)

How is valganciclovir converted to ganciclovir?

via carboxypeptidase

Relationship between famciclovir and penciclovir?

famciclovir = oral prodrug → penciclovir

How are they administered?

Famciclovir = PO, Penciclovir = topical

How is famciclovir converted to penciclovir?

step 1 - carboxypeptidase; step 2 - xanthine oxidase

Which drug covers HSV, CMV, and VZV?

ganciclovir

Which viruses do acyclovir-class drugs mainly treat?

HSV + VZV (limited CMV); only ganciclovir covers CMV

What major change improved HCV outcomes?

direct-acting antivirals (e.g., sofosbuvir) ↑ cure rates dramatically

MOA of sofosbuvir?

RNA-dependent RNA polymerase inhibitor (NS5B), chain terminator

MOA of velpatasvir?

NS5A inhibitor → disrupts replication machinery; synergises with sofosbuvir

What key structural feature made sofosbuvir effective?

2′-methyl + 2′-fluoro modifications

What enzyme does sofosbuvir inhibit?

viral RNA-dependent RNA polymerase (RdRp)

How is sofosbuvir activated?

prodrug → monophosphate (via CES1/HINT1) → triphosphate (active)

Why does sofosbuvir inhibit RNA synthesis despite having 3′-OH?

steric hindrance (methyl/fluoro) disrupts elongation

How do physical properties affect drug design?

↑ polarity → ↓ bioavailability; prodrugs improve absorption

What determines antiviral toxicity?

selectivity for viral vs host polymerase