Exam 4 - Stahelin PIs (study)

Question 1

Recognize the structure of HIV PIs atazanavir and darunavir and point out the non-cleavable bonds.

Answer 1

amide bond?

Question 2

How does the structure of tipranavir, a non-peptidomimetic PI, differ from the others?

Answer 2

-no peptide backbone
-triple F group

Question 3

MOA of PIs blocking HIV protease activity.

Answer 3

inhibitor binding causes a conformation change in protease - ‘flaps’ close

Question 4

Describe how resistance to PIs arises. How can we minimize the the viral strains resistant to PIs?

Answer 4

-can be in active site or far away
-modify contacts btwn protease and inhibitor: reduce affinity of protease for inhibitor
-protease inhibitors bind tightly to protease
-natural substrates have variable, less tight binding
-resistance mutations have greater effect on PI than natural substrate

Question 5

How do darunavir and atazanvir differ from other protease inhibitors with regards to PI resistance mutations?

Answer 5

They can inhibit both wild type and mutants that are resistant to other PIs. This is due to the peptide backbone so it is less affected by changes in amino acid side chains.

Question 6

Describe how the effect of protease inhibitors on CYP3A4 can be exploited for anti-retroviral therapies. (What is PI boosting and how is it used?)

Answer 6

Low doses of ritonavir can inhibit CYP3A4
-block metabolism of other PIs, increases serum concentration of these PIs
-lopinavir and tipranvir are not indicated for use except in combo with ritonavir

Question 7

Describe the structures of ritonavir and cobicistat act on CYP3A4 to act as PI boosters.

Question 8

State the currently recommended initial anti-retroviral drug regimen.

Answer 8

Biktarvy
Triumeq
Dovato
Genvoya

Question 9

Name all the PIs

Answer 9

atazanavir
darunavir
tipranavir

Question 10

AE of all PIs

Answer 10

-hyperlipidemia
-insulin resistance and diabetes
-lipodystrophy
-elevated LFTs
-possible bleeding risk
-drug-drug interactions