Protease
inhibitors
The HIV protease works by
cutting up long chains of the virus' proteins and enzymes (polyproteins) into
smaller pieces that go on to infect new cells. Protease inhibitors bind to the
HIV protease and, whilst bound, prevent the enzyme from cutting the viral
protein molecules to their correct sizes. This means the virus cannot make
copies that can infect new cells. This all occurs near the end of the life
cycle of the virus.
Most of these drugs are peptide-mimicking
compounds. In other words, these compounds resemble the natural
substrate of the HIV
protease. The inhibitors bind to the enzyme much more tightly than
the natural substrate.
The protease
inhibitors can slow virus production in both newly infected cells
and cells that have been infected for a long time, this is different to the NRTIs
and NNRTIs which only work on cells that have been infected for a short time.
Nucleoside
Analogue Reverse Transcriptase Inhibitors
Nucleoside Analogue Reverse Transcriptase Inhibitors
(NRTIs) were the first type of drug available to treat HIV infection. Not
surprisingly, NRTIs inhibit the enzyme reverse transcriptase. NRTIs
are analogs (think of the word "analogous," which means
"similar") because they are imitations of the body's
own nucleosides, which HIV uses to infect
cells.
Non-Nucleoside
Reverse Transcriptase Inhibitors
Like NRTIs, the non-nucleoside reverse transcriptase
inhibitors (NNRTIs) also keep HIV from infecting cells
by interfering with the virus' reverse transcriptase. However, they do it in a
different way. The NNRTIs
bind directly to reverse transcriptase, which changes the shape of the enzyme.
This means the enzyme cannot interact normally with the viral RNA to produce
DNA. They are metabolized in the liver, so if used there must be special
consideration of potential interactions with other drugs that are also
processed through the liver.
Entry
Inhibitors
To enter a host cell, HIV
must bind to two separate receptors on the cell’s surface. First, the gp120
glycoprotein on HIV’s envelope binds to the CD4 receptor, which is present on
various types of immune cells including CD4 T-cells. When this is
accomplished, gp120 must then bind to a second co-receptor. HIV-1
can use two chemokine co-receptors, CCR5 or CXCR4. Once HIV has attached to
both CD4 and a co-receptor, its envelope can fuse with the host cell membrane
and release viral components into the cell.
Researchers have investigated several potential
therapies that act at various stages of viral entry including fusion
and co-receptor attachment. Blocking any step of the entry process can
interfere with HIV
replication. This is even more effective when entry inhibitor
drugs that work by different mechanisms can be used together.
Integrase
Inhibitors
Along with reverse transcriptase and protease, a third
HIV
enzyme – integrase – is essential for viral replication. Integrase is
responsible for inserting viral genomic DNA into the host chromosome.
The integrase
enzyme binds to host cell DNA, prepares an area on the
viral DNA for integration, and then transfers this processed strand into the
host cell’s genome.
There are various types of integrase
inhibitors, including diketo acids, napthyridines,
pyranodipyrimidines, and dihydroxythiophenes.
Maturation
Inhibitors
After new viral enzymes, proteins, and genetic
material are produced and processed, they must be packaged together into new
viral particles. These components are first enclosed in a capsid, which is then
surrounded by an envelope as it ‘buds’ out of the cell to become a complete
virion. As with the other steps of the HIV life-cycle, viral
assembly and maturation offer several potential targets for new therapies.
To meet the International Experts in the field of
STDs, visit: https://std-hiv-aids.cmesociety.com/
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