31 - herpes ii Flashcards
what is strategy 2 in increasing the selectivity of an antiviral
chain termination
explain the process of chain termination in an antiviral drug
- make a molecule that can get incorporated into the stand of DNA but you design it so that whatevers at the 3’ position is a non-nucleophilic OH isostere
- if its similar enough, polymerase will accept it into the structure, but once its there the replication basically stops
what does combining non-natural base and chain termination do
achieve high selectivity
what are the requirements for chain termination
- Drug is phosphorylated (host or virus)
- must be similar enough to the normal base
- Drug a substrate for viral polymerase
- Gets incorporated into viral nucleic acid
- Stops replication, get a short piece of nucleic acid
- Viral proteins don’t get made
- Drug must NOT be a substrate for host polymerase
- Side effects!
describe the selectivity challenge in a virally infected cell vs a healthy cell
viral: first step again is getting phosphorylated, accepted by the polymerase = stop replication, and if we’re lucky kill the cell
healthy cell: - ideally your drug does not get phosphorylated in the healthy cell
- if the drug does get phosphorylated in the healthy cell, it will just build up and cause eventual problems
- most important thing is that we dont want it to get targeted by the host polymerase
why is selectivity a problem with chain termination
- Drugs have structures that are too similar to normal substrate
- Occasionally, these drugs get incorporated into host nucleic acid by the host polymerases
- Many chain terminators are toxic
- often carcinogenic
how can changing the sugar in an antiviral improve selectivity
- technique discovered in the 1970s
- by changing the structure of the sugar you can get a molecule that acts as a chain terminator but is much more selective
- realized that normal nucleosides have rigid sugar, so they made it more flexible by cutting open the ring
- has the right OH groups in the right places = read by polymerases, but because they are floppy, they will be in the wrong orientation to carry out chain synthesis
what strategy does acyclovir use and how are its side effect and selectivity
strategy 2 - chain terminator
- Very high selectivity for virally infected cells
- by virtue of its structure
- Low incidence of side effects
- Low severity of side effects
- Selectivity is primarily due to selective bioavailability
how is acyclovir a prodrug and what effect does this have on its bioavailability
- bioavailability comes about because it is a prodrug
- in order to become activated, it needs to become phosphorylated
why is acyclovir only activated in virally infected cells
- herpes has its own kinase - thymidine kinase
- thymidine kinase has the ability of adding one phosphate group onto Acyclovir = prodrug form = phosphorylated drug form
- selectivity here happens because the host kinase cannot phosphorylate acyclovir = no reaction, drug stays in inactive form
- drug never gets activated unless you are having an active infection with your virus
describe the phosphorylation of acyclovir
- first phosphorylation is done by thymidine kinase (herpes)
- as soon as you add one phosphate to acyclovir, the human kinases now have the ability to add phosphates.
- two human kinases that add phosphates (guanylate kinase, phosphoglycerate kinase)
- after three phosphorylations, you end up with the triphosphate structure
why does acyclovir have the ability to diffuse in-and-out of normal cells
- if you gave this drug to a person, it circulates randomly throughout a persons body and has the ability to go into host cell
- because its just in the prodrug form it has the ability to diffuse out of the cell
how does phosphorylation “trap” acyclovir in infected cells
- when acyclovir randomly goes inside a cell that is infected with herpes, the thymidine kinase adds a phosphate group onto it
- the phosphate groups stays negatively charged because it is too difficult to protonate it
- very soluble, stays in the cell
- cannot pass through a membrane
- the phosphate groups stays negatively charged because it is too difficult to protonate it
- then host enzymes add two more phosphate groups
- the drug has three negative charges on it
- basically imprisoned to the viral cell
- the drug has three negative charges on it
what principle causes acyclovir to concentrate in infected cells
- drug can only diffuse in and out of cells if it is neutral
- as the enzymes phosphorylate the drug more and more, more of the drug becomes sucked into the viral cell by le chatelier’s principle
- basically taking all of the drug from the normal cell and sucking it into the infected cell, converting it into the active form
describe the properties that makes acyclovir a clean drug
- Circulates randomly in the body
- Accumulates only in virally infected cells
- Drug concentration in normal cells is too low to cause problems
- Few side effects
- Low incidence of side effects
