Antiviral Chemotherapy 1 - NRTI + NNRTI Flashcards
(24 cards)
What are the 3 main enzymes in HIV?
Integrase
Reverse transcriptase
Protease
Describe reverse transcriptase
First uses RNA then DNA as a template
Endonuclease activity = degradation of the RNA strand of the RNA/DNA hybrid
Needed for transcription of viral genome
Describe process of reverse transcriptase
Reverse transcriptase = reading RNA + making complementary strand
RNase H/Reverse transcriptase = chop out RNA = 2nd strand of DNA = double strand
Integrase = insert into host cell genome
What is the structure of reverse transcriptase?
Heterodimeric enzyme
2 polypeptides
p51 unit lacks the RNase functional region
Described as a right hand with palm, fingers + thumb
Describe the chemistry of reverse transcriptase
3’-OH (strong Lewis base) of primer terminus lies in proximity to a triad of aspartic residues in active site
2Mg2+ (strong Lewis acid - in active site) = interact with triphosphate + 3’ terminus of primer
Describe the right hand structure model
Fingers = provide a channel = can move
Thumb = involves translocation = hold on genetic material + moving
Catalytic aspartates = hold 2 metal ions
What are the 2 classes of reverse transcriptase inhibitors?
Nucleoside inhibitors (NRTIs)
Non nucleoside inhibitors (NNRTIs) = these bind at hydrophobic pockets adjacent to active site
How does NRTIs work?
Analogues of endogenous 2’-deoxy-nucleosides/tides
Must be phosphorylated = active = anti-viral effect
Cell full of kinase - phosphorylate
Hydrophilic = limited membrane permeability = transported into cell via solute carrier transporters
Lack 3’-hydroxyl group - prevent chain elongation = chain-terminators
What is a problem with NRTIs being phosphorylated?
Significant SEs = potential toxicity with mitochondrial polymerase enzymes
What was the first NRTI?
AZT
= acts via triphosphate metabolite to inhibit RT
What is reverse transcriptase downfall?
Has no proof reading
= drug attaches
= can’t reverse it
What is HARRT?
Highly active antiretroviral therapy
= initiated with 2 NRTIs + 1 NNRTI
Who is 2 NRTI + protease inhibitor for?
Resistance to 1st line
Women wishing to become pregnant
Psychiatric disorders
What is the metabolism + toxicity associated with NRTIs?
Majority dose excreted unchanged = highly polar drugs
Toxicities associated with inhibition of mitochondrial polymerase-gamma = increased plasma lactate
What is the chemistry for Tenofovir?
LogP = -4
Orally available at LogP = 0-5
= a pro-drug
Describe Tenofovir Disoproxil Fumarate (pro-drug)
Improved cell permeability = orally available
BUT associated with effects on renal function + BMD
Renal accumulation = efficient uptake from plasma = reduced efflux into urine
Describe Tenofovir Alafenamide (pro-drug)
Higher delivery target cells
Reduced kidney damage
Reduced bone demineralisation
Where does NNRTIs bind?
Allosteric binding site
How does NNRTIs work?
Pocket = hydrophobic
Causes conformational change = causes movement of aspartic acid residues in active site
= inhibiting enzyme
Slightly decreases function of RNase
Describe the structure of 1st generation of NNRTIs
Rigid structures = fixed structure (planar)
Describe the structure of 2nd generation of NNRTIs
Flexibility = rotation around the bonds
= can still bind with resistant strains
What are NNRTIs metabolised by?
CYP3A4
Describe the pharmacodynamics + physiochemical properties of Rilpivirine
pKa = 5.6 (weak base)
Poorly H2O soluble
Lower incidence of CNS effects
NOT recommended for breastfeeding mothers
Describe the pharmacodynamics + physiochemical properties of Doravirine
pKa = 3.51 (acidic centre)
Quickly absorbed after oral (not impacted by food)
Pharmacokinetics NOT affected by age, gender or ethnicity
NO dose adjustment for patients with hepatic impairment
