Antiviral Chemotherapy 3 - Protease Inhibitors Flashcards
What is the role of HIV protease?
Cleavage of viral peptides
Large protein inserted into host genome = cuts it up into smaller
What are the different types of proteases?
Peptidases = cleave single amino acids from end of chain
Proteinases = cleave peptide bonds within a substrate
What is HIV protease responsible for?
Cleaving amide bonds
Describe HIV protease structure
Homodimer (2 identical polypeptide chains)
With only one active site
Acts as “chemical scissors” to cleave polyproteins into functional constituent proteins
Describe the structure of HIV protease
Quaternary with 3 domains
Dimerization domain
Core domains
Flap domains
Describe the core domain
Conserved Aspartate (essential for catalytically + structurally), Threonine + Glycine catalytic triad (active site)
At interface of core domains from 2 monomers
Describe the importance of Asp
Asp25 + Asp25’ plus water molecule = general acid/base amide hydrolysis = catalysis
Describe importance of water
OH taken across the bond
= bond cleaved
H2O = better nucleophile
What is useful about Phe-Pro?
Recognised by HIV protease enzyme = protease knows where to cut
How does protease inhibitors work?
One OH = molecule has isostere for amide
BUT NO 2nd OH = HIV can’t complete cycle
Describe how Tipranavir works
Displaces H2O molecules from active site = stops activity of the enzyme
Describe ADME of protease inhibitors
Food has important effect of A
CYP450 = M
Describe the interactions if PI
Medications that inhibit CYP450
= increase conc of PI
Caution with ketoconazole, rifabutin + methadone
Avoid St John’s Wort (CYP450 inducer)
Why is Ritonavir important?
Inhibits CYP450 3A4
Reduces metabolism of concomitantly administered PI
= improves bioavailability
Why is Cobicistat important?
Booster with NO antiviral activity
BUT does increase serum creatinine conc
