Lecture 16 - Structure Activity of Antivirals Flashcards
Key enzymes in HIV?
protease
reverse transcriptase
integrase
What are nucleoside reverse transcriptase inhibitors?
they mimic the natural nucleosides that are incorporated into the double helix chain formation of DNA-RNA and DNA
What type of drugs are nucleoside reverse transcriptase inhibitors?
prodrugs metabolised to give non-functional nucleotides
What happens when NRTIs are incorporated into the growing chain?
it causes chain termination
What does chain termination cause?
no more HIV can be made and CD4 cells are not further compromised
What happens when a nucleoside is phosphorylated?
it becomes a nucleotide
there are 3 phosphate groups required for the molecule to be incorporated into the growing chain
Examples of NRTIs?
deoxythymidine
zidovidine
What is the key part of an NRTI molecule?
the azide
What is required to make the growing chain?
a neighbouring hydroxyl group from another nucleosides, attacks and makes the growing chain
Further examples of NRTIs?
lamivudine (epivir)
zalcitabine (Hivid)
stavudine (Zerit)
abacavir (Ziagen)
didanosine (Videx)
emtricitabine (emtriva)
What are the two targets of NRTIs?
protease and reverse transcriptase
What is remdesivir?
an NRTI used in covid-19
What does the hydroxyl group on remdesivir do?
this is a non obligate chain terminator
although it may bond to another nucleoside, it does NOT
What does the adenosine like moiety in remdesivir do?
it is involved in base paring with uracil
this is very similar to how adenosine makes base pairs, this is possibly why it gets incorporated by viral polymerase
What is the ‘glycosidic bond’ in remdesivir?
normally is from ribose C to a base N
in this it is C-C and so it is more stable against nucleases as it is not a hemi-aminal bond
What does the cyano group in remdesivir do?
provides less toxicity as it is not incorporated into the host polymerases
only possible by iterations and cell evaluation
What is the phosphamide in remdesivir?
protide protecting group
more lipophilic than monophospate helping uptake across the cell membrane
What does the phosphamide group on remdesivir help with?
activation at first and the difficult, kinase phosphorylation (first phosphate group) is already done
What are non-nucleoside reverse transcriptase inhibitors?
known as allosteric inhibitors
bind to a lipophilic pocket at the base of the thumb area of the RT enzyme
How do NNRTI’s work?
conformationally prevents the enzyme from allowing the single strand of RNA to be transcribed
prevents replication and protects CD4 cells
What do 1st generation NNRTIs have?
butterfly wing lipo, H bond and pi pi stacking
What do 2nd generation NNRTIs have?
horse shoe like shape
What do NNRTI’s target?
polymerase during transcription as allosteric inhibitors
What is made following transcription and translation?
large proteins
What makes a virion?
when these large proteins are processed into smaller proteins
What does protease do?
cleaves the larger proteins, hydrolysis of the protein peptide bond
What is HIV protease?
a much smaller enzyme than the equivalent host aspartate proteases
What does HIV protease do?
cleaves substrates N terminal to proline residues unlike mammalian proteases
What is the cleave site for HIV protease?
Try-Pro
What was the rationale for inhibitor design based on?
Phe-Pro or Tyr-Pro motif
What do protease inhibitors do?
mimic the substrate with non-hydrolysable functionality
Examples of protease inhibitors?
ritonavir
indinavir
saquinavir
Drug used in the herpes simples and varicella zoster infection?
aciclovir
Example of an NNRTI?
nevirapine
