PS01 - Antiviral Agents Flashcards
What are the six stages of viral replication?
Attachment Entry Uncoating Macromolecular Synthesis Assembly Release
What is the MoA of Aciclovir?
Aciclovir is an analogue of Deoxyguanosine, but without a 3’ hydroxyl group
Both a 5’ and a 3’ hydroxyl group are required for the replication of DNA
Without the 3’ group DNA synthesis comes to a halt
How is Aciclovir selectively toxic?
Aciclovir has to be triphosphorylated to have its DNA chain termination effect
The initial phosphorylation is performed by HSV-TK (thymidine kinase)
HSV-TK is present in viral cells but not eukaryotic cells
What determines the cellular uptake of Aciclovir into specifically viral cells?
Diffusion down a concentration gradient
What three factors determine the selective toxicity of Aciclovir?
Only active in viral cells (HSV-TK)
Concentrated in viral cells
Higher affinity for viral DNA polymerase
Describe the spectrum of activity of Aciclovir
Narrow, only targets HSV1/2 and VZV
Only these families possess HSV-TK
How does resistance to Aciclovir arise?
Absence of Thymidine Kinase (TK-ve)
Alteration of Thymidine Kinase
Exist pretreatment, appear during therapy
Alteration of DNA polymerase
Why is Aciclovir resistance due to TK absence not a clinical issue?
Because the absence of HSV-TK renders the variants non-pathogenic
Alteration strains are also attenuated
What Aciclovir resistance mechanism is clinically important?
Alteration of DNA polymerase, strain is fully virulent
In what population is Aciclovir resistance a huge clinical problem?
AIDS patients suffering from repeated HZV infections
What is Valaciclovir?
A variant of aciclovir joined to a valine ester
What is the key property of Valaciclovir?
Valaciclovir has a much higher oral bioavailability than aciclovir
What is Penciclovir?
An antiviral agent which acts as a viral DNA polymerase inhibitor but is not a chain terminator
How does primary oral herpes present?
Painful, white lesions on the tongue and soft/hard palate
Where does herpes virus lie dormant?
Trigeminal ganglion
How does recurrent oral herpes present?
Cold sores
In what situation is treatment of oral herpes clinically justifiable?
Treatment of primary oral herpes ONLY
How does primary genital herpes present?
Painful, white lesions on the genitalia
How does recurrent genital herpes present?
Fewer, less painful lesions
In what situation is treatment of genital herpes clinically justifiable?
Treatment of primary genital herpes
Prophylaxis for frequent, severe, atypical genital HSV
How is treatment of atypical recurrent genital herpes managed?
Long term therapy
Titration of dose down to eventual cessation
What is herpes simplex encephalitis?
Inflammation of the cerebral hemispheres due to infection with HSV
How is herpes simplex encephalitis treated?
Immediate administration of i.v. aciclovir
What other forms of HSV can be treated with Aciclovir?
Ocular herpes simplex
Eczema herpeticum
What diseases are caused by Varicella Zoster Virus?
Chickenpox
Shingles
When is Aciclovir used to treat chickenpox?
In adults, often suffering from Varicella Pneumonia (i.v. aciclovir)
What complications can chickenpox cause in pregnancy?
Increases risk of varicella pneumonia
Should aciclovir be used in pregnancy?
In life threatening situations ONLY
Worries of teratogenesis as DNA synthesis inhibitor but safe record
Where does VZV go latent?
Nerve cell bodies in the spinal cord and cranial nerves
How should reactivated VZV (shingles) be treated?
Immediately w/ i.v. aciclovir in immunocompromised and most other patients
What is disseminated voster?
Unusually widespread herpes zoster in immunocompromised patients
What is the main problem with Aciclovir/Aciclovir like drugs?
They have a very narrow spectrum of use
Why can Aciclovir not be used in Cytomegalovirus?
CMV does not posses HSV-TK so cannot phosphorylate aciclovir
What antiviral can be used to treat CMV?
Ganciclovir, a drug with a similar MoA to aciclovir but that is initially phosphorylated by UL97
Against which herpesviruses is Ganciclovir active?
All herpesviruses
What are the disadvantages of Ganciclovir?
Poorly absorbed orally (use valganciclovir)
Toxic, often in bone marrow (less selective for viral cells)
What is Cidofovir?
An acyclic phosphanate nucleotide analogue used as an antiviral to treat CMV retinitis
What is the MoA of Cidofovir?
Same as Aciclovir (DNA chain terminator) but with the first phosphate already added
What is the disadvantage of Cidofovir?
Less selective for virally infected cells
Leads to greater toxicity (nephrotoxic)
What is the advantage of Cidofovir?
Can inhibit any viral DNA polymerase (potentially)
What is Adefovir?
An analogue of Cidofovir used to treat chronic Hep-B infection
What is Foscarnet?
A pyrophosphate analogue used as an antiviral agent
What is the MoA of Foscarnet?
Inhibits DNA polymerase as it forms phosphodiester linkages in the DNA chain
What are the disadvantages of Foscarnet?
Poor oral availability
Nephrotoxic
What are the three CMV antiviral agents?
Cidofovir
Ganciclovir
Foscarnet
What is Ribavirin?
A nucleotide analogue used as an antiviral agent
What is the MoA of Ribavirin?
Not entirely known
Possibly interferes w/ mRNA processing
Possibly acts as a mutagen
For what viruses is Ribavirin effective?
Severe RSV infection (inhalation)
Lassa fever
Chronic hepatitis C (w/ IFN)
How do Uncoating Inhibitors work?
They inhibit the uncoating of the viral nucleic acid from its protective nuclear capsid
Give two examples of Uncoating Inhibitors
Amantadine
Rimantadine
What viruses is Amantadine treatment effective for?
Influenza A only
What is the MoA of Amantadine?
Amantadine acts to block an ion channel created by one of the matrix proteins of Influenza A, preventing uncoating
What are the disadvantages of Amantadine treatment?
Only effective in Influenza A
Poorly tolerated (CNS stimulation)
Resistance rapidly emerges
How does resistance to Amantadine arise?
A SNP in the matrix protein, preventing Amantadine binding
What two glycoproteins are studded throughout the viral lipid envelope?
Haemagluttinin
Neuraminidase
What is the function of Neuramindase?
Cleaves the glycosidic linkages of neuraminic acids, allowing for the release of virions from infected cells
What is the MoA of Neuramindase Inhibitors?
Compounds that bind to the active site of Neuramindase and inhibit it, preventing the release of virions from infected cells
Give two examples of Neuramindase Inhibitors
Zanamavir (inhaled)
Oseltamivir/Camiflu (oral)
What are Neuraminidase Inhibitors used to treat?
Severe influenza infection
Influenza infection in high risk individuals
What is the advantage of Neuraminidase Inhibitors?
Work against all known influenza NA
In which strain of influenza has resistance to Neuraminidase Inhibitors been demonstrated?
H5N1 (avian) w/ H274Y mutation
