Su: Anti-HIV Protease Inhibitors

Lecture 1

name the HIV protease inhibitors

Saquinavir, Ritonavir, Indinavir, Fosamprenavir, Lopinavir, Nelfinavir, Tipranavir

what is the suffix for HIV protease inhibitors?

-navir

HIV protease is responsible for ____of core proteins into structural proteins

post-translational modification

HIV protease cleaves the viral ____ and ____ polyproteins into smaller functional proteins

Gag and Gag-Pol

what does the HIV gag gene code for

virus and the coat proteins

what does the HIV gag-pol genome code for

Codes for reverse transcriptase and other enzymes

If you inhibit the protein HIV protease it cannot _____ responsible for making the viral particle that spreads.

cleave the proteins

HIV protease is produced by the ____ gene

pol

what are the two options for blocking HIV protease or the Pol gene that makes it?

Terminator 1 - Target the gene before HIV protease protein is made.

Terminator -2 Terminate the HIV protease which helps to make the virus particle.

HIV protease is a _____ enzyme

symmetric dimer

what class does HIV protease belong to

aspartic protease

the drugs that inhibit HIV protease should not inhibit…

mammalian aspartic proteases

which CYP is the most important for metabolism of xenobiotics in the body

CYP3A4

where can you find the most CYP3A4 in the body

livah (liver)

most protease inhibitors act as substrates for _____

CYP3A4

the use of other drugs that are metabolized by CYP3A4 may be ____ if used with HIV protease inhibitors

contraindicated

the active site of HIV protease contains which amino acid sequence?

Asp-Thr-Gly

HIV protease cuts the ___ bond of proteins

amide

what specific amino acid sequence does the HIV protease cut at?

Ser(Thr)-X-X-Tyr(Phe)-Pro

Binding at the enzyme active site is specific, depends on ____

amino acids in the active site.

HIV protease undergoes mutation which leads to

alteration in active site residues and resistance is developed

mutation of ____ in the active site of HIV protease leads to decreased activity of the inhibitors

one or two amino acids

Mutation of one or two amino acids in the active site leads to ____

decreased activity of the inhibitors

mutation of ____ amino acids in the HIV protease leads to resistance to the inhibitors

5 or more

mutation of 5+ amino acids in the HIV protease leads to….

resistance to the inhibitors

where can mutations occur in HIV1 protease (generic answer)

Leu, Val, Ile, Ala, Met, Phe, Thr

brand names of saquinavir

fortovase and invirase

saquinavir is used for…

advanced HIV infection

saquinavir can be used in pts who did not receive ___ or who had prolonged treatment with ___.

ZDV (for both)

combo therapy of saquinavir with ___ seems to have better effects than ____ alone

ZDV or ddC (for both blanks)

bioavailability of saquinavir

4%

hella water insoluble

metabolization of saquinavir

glucuronidation in the liver (small amount tho)

what drug is this

saquinavir

where are the amide bonds on saquinavir

what drug is this

ritonavir

brand name of ritonavir

norvir

what does ritonavir inhibit

both HIV1 and HIV2 proteases

ritonavir can be used alone or in combo with ____ to increase CD4 counts

3TC, ZDV, Saquinavir or ddC

ritonavir can be used alone or in combo with 3TC, ZDV, Saquinavir or ddC to…

increase CD4 counts

how many metabolites of ritonavir are there?

5

where are most of ritonavirs metabolites found?

urine and feces

which CYP metabolizes ritonavir

CYP3A4

ritonavir cannot be used with which drugs due to contraindication

clarithromycin, desipramine, ethinyl estradiol, rifabutin, and sulfamethoxazole-trimethoprim (aka bactrim)

where are the amide bonds on ritonavir?

how many amide bonds does ritonavir have

3

how many thiazole rings does ritonavir have?

2

where are the thiazole rings on ritonavir

all metabolites of ritonavir are more _____

water soluble

brand name of indinavir

crixivan

what drug is this

indinavir

indinavir can be given in combo with ____

ZDV and ddl

resistant to ____ is possible in some strains of HIV

indinavir

indinavir is not an inhibitor of ____

reverse transcriptase (duh its a protease inhibitor)

why can indinavir be taken with other nucleoside drugs

bc its not a reverse transcriptase inhibitor

what is the dosing interval used for indinavir

q8h

indinavir is metabolized via which reactions

oxidation and glucuronide conjugation

how many metabolites of indinavir are there

7

why does indinavir have hella drug interactions

bc it inhibits CYP3A4, CYP3A5, CYP3A7

where is the amide bond on indinavir

explain the metabolism of indinavir to M1

oxidative N -dealkylation (removal of the indene group)

explain the metabolism of indinavir to M2

oxidative N-dealkylation (removal of the purine)

explain the metabolism of indinavir to M3

hydroxylation of the fused benzenes after M2 ahs been formed

explain the metabolism of indinavir to M4

para hydroxylation of mono-substituted benzene compounds

explain the metabolism of indinavir to M5

hydroxylation of fused benzenes

explain the metabolism of indinavir to M6

N-oxidation of aromatic nitrogen

what drug is this?

amprenavir

what is the brand name of amprenavir

agenerase

where is the amide bond on amprenavir

what drug is this

fosamprenavir

what is the brand name of fosamprenavir calcium?

lexiva

fosamprenavir is a ___ of the protease inhibitor and antiretroviral drug amprenavir

pro-drug

where are the amide bonds on fosamprevnavir

what drug is this

nelfinavir

where are the amide bonds on nelfinavir

what is the brand name of nelfinavir

viracept

what drug is this

lopinavir

brand name of lopinavir

kaletra

where are the amide bonds on lopinavir

kaletra (lopinavir) is a co-formulation that contains ____

ritonavir

what drug is this

atazanavir

where are the amide bonds on atazanavir

what drug is this

darunavir

where are the amide bonds on darunavir

tipranavir is also called

tipranavir disodium

tipranavir is a ______ protease inhibitor

non-peptidic

tipranavir inhibits the replication of viruses that are _____

resistant to other protease inhibitors

who is recommended to get tipranavir

pts who are resistant to other strands

resistance to tipranavir requires ____ mutations

hella