antivirals

• describe the steps of the viral replication cycle

  attachment - virus becomes attached to a target epithelial cell

  penetration - the cell engulfs the virus by endocytosis

  uncoating - viral contents are released

  biosynthesis - viral RNA enters the nucleus where it is replicated by the viral RNA polymerase

  protein synthesis, protein maturation and virion assembly

  release - new viral particles are made and released into the extracellular fluid while the host cell continues to make new viruses
• what is the difference between viral targets and host cell targets?

  Viral targets: specific components of a virus that can be targeted for treatment. Host cell targets: specific components of a host cell that can be targeted for treatment.
• what are the pros and cons of viral targets?

  pros = selective agents and reduced toxicity

  cons = risk of drug resistance
• what are the pros and cons of host targets?

  pros = lower risk of resistance and broad spectrum

  cons = risk of toxicity and side effects
• how do viral attachment inhibitors work?


  prevent the virus from entering - may block the receptors on the cell surface to prevent the virus from undergoing conformational change and entering the cell
• how do viral penetration inhibitors work?


  can bind to gp41 in HIV preventing the fusion of the HIV envelope with the host cell membrane
• how do viral uncoating inhibitors work?


  Prevent viral genome release by preventing the activation of the M2 protein which would ordinarily allow protons to enter the endosome and allow viral contents to enter the cell as a result
• what are the 2 classes of viral polymerase inhibitors?


  nucleoside inhibitors (NIs) and non-nucleoside inhibitors (NNIs) - this is NRTIs and NNRTIs for HIV virus in particular
• how do NIs work?


  inhibit viral polymerases by competing with the natural substrate (dNTP or rNTP)

  they are then incorporated into the growing nucleic acid chain to terminate/hijack elongation

  they must be activated by phosphorylation by host/viral kinases to the triphosphate form
• how do NNIs work?

  bind viral polymerases at an allosteric site

  binding induces conformational changes causing inactive enzyme conformation, therefore indirectly inhibiting the catalytic function

  they DO NOT require phosphorylation or activation
• what is the difference between nucleosides and nucleotides?

  nucleosides do not have phosphate chains whereas nucleotides have phosphate chains which are up to 3 phosphates long (e.g. ATP)
• how are NIs activated?

  viral enzymes add a phosphate group to the drug (e.g. aciclovir) and then human enzymes add 2 more phosphates of the drug to produce a triphosphate of the drug (e.g. aciclovir triphosphate)

  during viral DNA replication, the drug is added to the growing strand rather than the nucleos(t)ide it mimics = further elongation of the DNA molecule is halted and viral replication stops

  
  

  note: the drug can also replicate a chain terminator as is the case in HIV
• what are the limitations of NIs?


  slow activation to monophosphates, rapid deactivation, active transport required and can often be quite toxic
• what are the pros/cons of using nucleotide inhibitors instead of nucleoside inhibitors?

  nucleotides = bypass first activation step but has poor cell penetration

  phosphate group has to be masked

  several prodrug strategies in order to mask the phosphate - prodrugs known to have poor oral absorption though
• what are the requirements for the masking groups?

  ideally, they are lipophilic, stable in plasma, hydrolyse in cells and produce non-toxic byproducts
• what are the characteristics of HIV?


  2 types - HIV-1 and HIV-2 - it can cause AIDS which causes progressive failure of the immune system, allowing life-threatening opportunistic infections and cancers to survive
• what are the stages of HIV?

  1 = acute HIV - flu-like symptoms that occur days to weeks after contracting HIV

  2 = chronic HIV - latent and asymptomatic stage - can last several years

  3 = AIDS - occurs when CD4 cell count falls below 200 - patients are vulnerable to opportunistic infections and AIDS-defining conditions

  NOTE - if HIV infection is not treated - median time from infection ot development of AIDS is 8-10 years - HIV must be treated.