Anti-virals (9.1)

Question 1

Aciclovir

Answer 1

Purine analogue, competes with GTP. DNA chain terminator

Activation: Thymidine kinase - ONLY found in virally infected cells

MoA: A nucleoside which competes with guanosine (a purine) triphosphate (GTP) for binding to viral DNA polymerase. Its lack of a 3’ OH group prevents chain elongation (phosphodiester bond cannot be formed), causing DNA termination

Spectrum of activity: Narrow

• Only active against DNA viruses which possess thymidine kinase - this is only the herpes simplex family, specificially HSV and VZV

Selectivity of action:

• Activated in infected cells
• Concentrated within infected cells
• Higher affinity for viral DNA polymerase than cellular enzymes.

Resistance:

• Absence of thymidine kinase
  
  • TK^- variants - not pathogenic
• Alteration of thymidine kinase
  
  • TK mutants - less pathogenic, cause less disease
• Altered DNA polymerase
  
  • Fully virulent
  • Arise in the context of immunosuppression. Use of prophylactic aciclovir leads to break through of resistant DNA polymerase

★ Opthalmic (Va) zoster infection should always be treated due to possible complications of the eye

Disadvantages:

Not effective against cytomegalovirus (CMV)

Question 2

Anti-cytomegalovirus drugs: Ganciclovir

Activation, MoA, spectrum of activity, disadvantages

Answer 2

Acyclic guanosine analogue

Activation: Requires phosphorylation (by UL97 - not thymidine kinase like aciclovir)

MoA: Once activated, ganciclovir triphosphate acts as a DNA polymerase inhibitor, preventing DNA chain elongation

Spectrum of activity: Active against all herpes viruses

Disadvantages:

• Poor oral absorption
• Easily phosphorylated, leading to serious side-effects in radidly diviiding tissues e.g. bone marrow

Question 3

Anti-cytomegalovirus drugs: Cidofovir

Answer 3

Acyclic phosphonate nucelotide analogue

Activation: Non-viral dependent phosphorylation

MoA: Inhibits viral DNA polymerase

Spectrum of activity: Broader spectrum. Potentially active against all DNA viruses

Disadvantages:

• Not absorbed orally at all. Required IV infusion
• Nephrotoxic HOWEVER no bone marrow toxiciity meaning it is suitable for use in bone marrow transplant

Question 4

Anti-cytomegalovirus drugs: Foscarnet

Answer 4

Pyrophospate analogue

MoA: Viral DNA polymerase inhibitor

Disadvantages:

• Poor oral availability
• Nephrotoxic

★ There are 3 CMV drugs. None are ideal. CMV infection is often seen in immunocompromised patients

Question 5

Ribavirin

Answer 5

A nucleoside analogue (prior to phosphodiester bond formation)

MoA: Interferes with the 5’ capping of mRNA, preventing the binding of mRNA to the ribosome for protein synthesis

Activity: Thought it would have a large spectrum of activity, against both DNA and RNA viruses

HOWEVER clinical use was disappointing, except:

• Severe RSV
• Lassa Fever (West Africa)
• Chronic HCV (+ IFN)

Question 6

Amantadine

Answer 6

MoA: Inhibits the uncoating of influenza A virus. Acts as an ion channel blocker (N2)

Disadvantages:

• Poorly tolerated due to CNS stimulation
• Resistance rapidly emerges due to N2 gene mutations

No longer recommended

Question 7

Neuraminidase inhibitors

Function of neuraminidase,MoA, advantages

Answer 7

Function of neuraminidase: Found the cell surface of influenza. An enzyme that acts to cleave the interaction between viral hemagglutinin and cellular sialic acid receptor, allowing the budding virus to leave the infected cell and begin to infect other cells

MoA: Acts to prevent neuraminidase from cleaving sialic acid - preventing the budding virus from leaving the host cell

Examples: Zanamavir and Oseltamivir (Tamiflu)

Advantages:

• Prophylactic use
• Effective against all known influenza NA - expected to be effective against next strains

Question 8

Aciclovir derivatives

Answer 8

• Valaciclovir: Much improved oral absorption in comparison to aciclovir (aciclovir is required to be taken multiple times daily)
• Penciclovir: Requires viral phosphorylation before being active

Question 9

Learning objectives:

• Describe the mechanisms of action, the basis of the selective antiviral toxicity, the antiviral spectrum, and the common clinical indications for the use of :
  a) Aciclovir
  b) The aciclovir derivatives Valaciclovir, Penciclovir and Famciclovir
  c) The anti-CMV agents Ganciclovir, Foscarnet, and Cidofovir
  d) Ribavirin
  e) The anti-influenzal drugs Amantadine and Zanamavir
• Describe the mechanisms underlying viral resistance to aciclovir.