Antivirals Flashcards
What are the stages of viral life cycle?
Adsorption onto host cell surface
Penetration into host cell
Synthesis of new genetic material
Transcription and translation into viral proteins
Assembly into virus particles
Liberation of virions from cell
What is the role of reverse transcriptase?
transcribes viral RNA into proviral DNA
DNA polymerase
- makes complementary DNA for the original viral RNA
= forms RNA-DNA hybrid
Nuclease (RNase H)
- cleaves the phosphodiester bonds to open the double strands
= leaves viral single strand DNA
reverse transcriptase
- generates complementary strand
= viral double strand DNA formed
How do nucleoside reverse transcriptase inhibitors (NRTIs) work?
mimic the natural nucleoside but have been modified so they do not posses the hydroxyl at C3
- NRTI is incorporated into the growing DNA strand by acting as a substrate for reverse transcriptase
- terminates the chain as subsequent nucleotides cannot be added
= does not have the hydroxyl at C3 required
What are the types of nucleoside reverse transcriptase inhibitors?
azidothymidine (AZT)
- acts as a thymidine mimic
- has an azido group (N3)
didanosine
- is metabolised to dideoxyinosine (DDL) which acts as an adenine mimic
- does not have a hydroxyl at C3
dideoxycytidine/zalcitabine
- acts a cytidine mimic
- does not have a hydroxyl at C3
emtricitabine
- acts a cytidine mimic
- has a fluorine group
lamivudine
- acts a cytidine mimic
- has a hydrogen atom
tenofovir
- acts an adenine mimic
How do non-nucleoside reverse transcriptase inhibitors (NNRTIs) work?
allosteric inhibition
- bind directly to reverse transcriptase at a distal site changing its structure
= non-competitive reversible inhibition
What are the types of non-nucleoside reverse transcriptase inhibitors (NNRTIs)?
nevirapine
delavirdine
efavirenz
How do HIV protease work?
is selective for HIV protease
- cleaves between aromatic residues (phenylalanine, tryptophan, tyrosine) and proline
= catalyses the hydrolysis of peptide bonds between proline and phenylalanine where the N-terminus of proline is linked to the C-terminus of phenylalanine.
How can mutation arise in NNRTIs?
resistance can arise due to a mutation where lysine is mutated to asparagine.
The HIV protease enzyme is symmetrical, whereas mammalian proteases are not. What significance might this have?
It may be possible to design inhibitors that prove selective for the HIV protease over mammalian proteases.
How do HIV protease inhibitors work?
Aspartic acid 25 and 25’ are involved in the catalytic mechanism which hydrolyses the peptide bond of a protein substrate
- are aspartic proteases
= cleaves the protease
What are examples of HIV protease inhibitors?
hydroxyethylamine
saquinavir
ritonavir
What is the HIV treatment regimen?
2 nucleoside reverse transcriptase inhibitors
- tenofovir, emtricitabine
1 other class of drug
- integrase inhibitor
= raltegravir
- non-nucleoside reverse transcriptase inhibitor
= nevirapine
