DDT 20 - Anti-retroviral drugs for the treatment of AIDS Flashcards
nucleoside
one of the building blocks to make RNA and DNA
HIV treatments
protease inhibitors
reverse transcriptase inhibitors
integrase inhibitors (optionally)
CCR5 receptor antagonist
How does HIV enter lymphocytes
HIV binds to 2 different receptors of lymphocytes
primary receptor - CD4
second receptor - CCR5 transmembrane protein, loops thru the cell membrane of T cell 7 times
HIV must bind to both receptors to infect cell
what events take place once HIV enters the cell
HIV viral RNA and the contents are empties into the host cell.
HIV takes over and makes many copies of itself
Reverse transcriptase function
enzyme that reads viral RNA entered in the host cell and transcribes the sequence into a complementary DNA sequence.
why are not all viruses alike
reverse transcriptase makes many mistakes when reading viral RNA sequence
may have different shape surface coat
function of integrase
helps insert the viral DNA transcribed from viral RNA into the host. Once the viral DNA is part of the host’s DNA it is called provirus
how many genes does HIV RNA have and what is the purpose of these genes
There are nine genes in the HIV RNA. These genes have all the necessary codes to make structural (viral envelope and core) proteins and enzymes (reverse transcriptase, integrase, and protease).
viral protease function
The translated viral RNA is made into a long polypeptide sequence which is made up of several individual proteins. These sections must be cut from the long polypeptide chain in order for the proteins (enzymes) to be functional.
assembly
viral RNA proteins leave the host cell taking the T-cell membrane containing viral surface proteins
name the 3 nucleoside reverse transcriptase inhibitors
azidothymidine (zidovudine)
stavudine (D4T)
abacavir (ABC)
Mechanism of action for azidothymidine and thymidine
lack 3’ OH on cyclic sugar
termination DNA chain elongation occurs
Non Nucleoside Reverse. Transcriptase Inhibitors (NNRTI) - Nevirapine
Nevirapine binds directly to RT. Thus it blocks RNA and DNA dependent polymerase activities disrupting the enzyme active site.
where does the nevirapine bind to?
These inhibitors have been shown to bind in a pocket formed between two beta-sheets of the p66 palm, ~10 Å away from the polymerase active site
is nevirapine hydrophilic or hydrophobic and name the amino acids it is made out of
The internal surface of this pocket is predominantly hydrophobic, being constructed primarily from leucine, valine, tryptophan and tyrosine residues.
another example of NNRTI
Efavirenz
How active is efavirenz and what kind of HIV does it work against?
Very active, also against wild type and resistant mutant of HIV-1.
It gives virus inhibition of 95%.
name HIV protease inhibitors
SAQUINAVIR, RITONAVIR, INDINAVIR are competitive antagonists of the natural substrate peptide
how does protease inhibitors work
The protease inhibitor binds to the site that normally binds the
protein chain. Once the inhibitor binds the protease cannot bind the
protein to be cleaved and is not functional.
what allows protease inhibitors to bind to protease
Protease inhibitors resemble the protein chain that the protease cuts
integrase inhibitors function
These compounds are designed to inhibit the Viral Enzyme Integrase, responsible for the integration of the Viral DNA in the Cell genome
integrase inhibitors examples
elvitegravir
dolutegravir
GS9160
PICA
compounds of name integrase inhibitors contain
Compounds of this class contain a b-ketoester or b-ketoamide
how do integrase inhibitors prevent the function of integrase
These compounds enter in the enzyme and go and coordinate to two essential Mg2+ cation that are involved in the catalytic cycle
give an example of a CCR5 Antagonist
Maraviroc
Maraviroc
Selectively binds to the human chemokine receptor CCR5, which is present on the cell membrane. This binding prevents the interaction of HIV-1 with CCR5-tropic HIV-1 and thereby inhibits the virus from entering the cell
