Anti-Virals 1: Herpes and Related Viruses Flashcards
Viruses – definition & general characteristics
LOOK AT THE VIRUS STRUCTURE
• Obligate intracellular parasites*
• Do not respire, move or grow
• consist of either DNA or RNA in a protective coat
(capsid) which directs viral replication.
• Contain/encode enzymes essential for replication.
• Progeny viruses are formed de novo from newly
synthesized components within the host cell
- poxviruses (smallpox)
- herpesvirus (chicken pox, shingles, oral & genital herpes)
- adenovirus (conjunctivitis, sore throat)
- Hepadenaviruses (hepatitis B)
- human papillomaviruses (warts, genitals)
what are these?
Examples of other DNA viruses
Replication cycle of herpes viruses
After infection, a small number of immediate-early genes are transcribed
- proteins regulate their own synth and synth early genes in genome replication (thymidine kinases, DNA pol)
- After DNA replication, the bulk of the herpesvirus genes (called late genes) are expressed and encode proteins that either are incorporated into or aid in the assembly of progeny virions
MORE
- attachment of virus
- uncoating and transfer of viral DNA to host nucleus
- viral DNA transcribed to viral mRNA
- protein synth by host cell ribosome
- proteins, enzymes lead to assembly of virion
- release
Human Herpes Viruses (HHVs)
• 8 types
- Herpes Simplex Virus-1 (HSV-1)
- Herpes Simplex Virus-2 (HSV-2)
- Varicella Zoster Virus (VZV)
- Epstein-Barr infectious mononucleosis
- EBV – associated with malignancy
- Cytomegalovirus (CMV)
HSV treatment
first agent?
what replaced it and why?
- First agent used was vidarabine (1977)
- Toxicity (teratogen, genotoxic) reserved this agent for life threatening infections
- Acyclovir (1982) replaced vidarabine
- Larger therapeutic window
- Superior efficacy in HSV encephalitis, and VZV.
- Genital and oral HSV infections.
- Ineffective against CMV
Acyclovir MOA
see pic for more
- similar structure to dGTP
1. Competitive inhibition of viral DNA pol
2. DNA chain term. Upon incorporation into primer strand - gives nonfunctional complex
HSV-1 TK phosphorylates acyclovir once, GMP kinase twice, NDP kinase three times to acyclovir-triphosphate
- GMP and NDP kinase are humans’
Selectivity depends on
• >200x for HSV TK than mammalian TK
• >inhibition of viral DNA pol than mammalian
Acyclovir vs Valacyclovir
L-valyl ester prodrug of acyclovir (1st-pass
metabolism forms acyclovir)
- acyclovir oral bioavailability (10-30%)
- valacyclovir ↑ bioavail to ~ 70% (substrate for intestinal and renal peptide transporters), ↑half-life
- Valacyclovir approved for VZV, HSV-1 & -2
Acyclovir resistance
• absence or partial production of viral thymidine kinase (HSV-1TK)
• altered thymidine kinase substrate specificity (e.g.,
phosphorylation of thymidine but not acyclovir)
• altered viral DNA polymerase
• Alterations in viral enzymes are caused by point mutations and base insertions or deletions in the corresponding genes
• the most common resistance mechanism in clinical HSV isolates is absent or deficient viral thymidine kinase activity
Penciclovir
what is the prodrug?
MOA?
- Famciclovir is the 6-deoxy diacetyl ester prodrug
- Use: HIV patients with HSV mucocutaneous infection.
- Similar spectrum of activity as acyclovir
- Some acyclovir resistant strain may be susceptible to Fam- and Penciclovir
- Penciclovir triphosphate - competitive inhibitor of viral DNA pol
- PK: penciclovir has low oral bioavailability (5%); famciclovir is better absorbed, & converted to penciclovir (65-77%).
- Resistance: thymidine kinase deficient viruses
- Toxicity: generally well-tolerated
Ganciclovir
- guanine nucleoside analog (related to acyclovir)
- USE: Especially active against CMV; similar potency as acyclovir against HSV.
- Phosphorylation – needed for activity (see above)
- viral thymidine kinase (HSV)
- Phosphotransferase/phosphokinase (CMV).
- The triphosphate metabolite is a competitive inhibitor of deoxyguanosine triphosphate incorporation into DNA and preferentially inhibits viral DNA pol
- PK: Low oral bioavail of ganciclovir (6-9%); 61% following valganciclovir
- Resistance: ¯intracellular phosphorylation due to mutant viral phosphotransferase; mutations in viral DNA polymerase
- Toxicity: myelotoxicity (neutropenia, thrombocytopenia); teratogenic in animals
Cidofovir
MOA?
- Main use: CMV infection; activity against HSV, papilloma, polyoma, pox, and adenoviruses
- Active against resistant HSV, CMV
• inhibits viral DNA synthesis (SIMILAR TO DCTP)
• Metabolized by cellular kinases to its active diphosphate metabolite*; similar levels in infected and uninfected cells
• Cidofovir-PPP is a competitive inhibitor and false metabolite for viral DNA pol.
prevents dCTP from being added
- Resistance: mutations in DNA pol.
- Toxicity: nephrotoxicity, neutropenia, rat carcinogen
Foscarnet
MOA?
- Use: CMV retinitis (AIDS patients) & acyclovir resistant HSV-1.
- Activity against HSV, CMV; mostly with ganciclovir-resistant CMV and acyclovir-resistant HSV and VZV strains
- Does not require phosphorylation for activity
- Active against viruses with deficient TK
- inhibits viral DNA pol at the PPi binding site (pyrophosphate)
- Blocks cleavage of the Ppi group from dNTPs -> halts polymerase
- PK: iv only. Renal excretion.
- Resistance: mutations in DNA pol.
- Toxicity: renal impairment – hypocalcemia. Prevent with hydration
Idoxuridine
MOA?
• Inhibits HSV-1 & -2 replication and poxviruses; topical
treatment of HSV keratitis
• Activated by cellular kinases
• Lacks selectivity; low concentrations inhibit the growth of uninfected cells
• triphosphate metabolite inhibits viral DNA synthesis;
incorporated in viral and cellular DNA
Trifluridine
MOA
- Trifluridine monophosphate (from cellular kinases) irreversibly inhibits thymidylate synthase
- trifluridine triphosphate inhibits vDNA pol.
- Widely used for treatment of primary keratoconjunctivitis and recurrent epithelial keratitis (HSV types 1 and 2).
- Of benefit to non-responders from idoxuridine or vidarabine treatment.
- Systemic toxicity – limited to topical use
Vidarabine
MOA
- Purine (adenosine) nucleoside analog
- Active against: HSV-1, 2, VZV, EBV
look like dAMP
vidaranine PPP inhibits vDNA pol
