The 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 . The inhibitors bind to the enzyme much more tightly than the natural substrate.
The can slow virus production in both newly infected cells and cells that have been infected for a long time, this is different to the s 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. are analogs (think of the word "analogous," which means "similar") because they are imitations of the body's own nucleosides, which uses to infect cells.
Non-Nucleoside Reverse Transcriptase Inhibitors
Like NRTIs, the non-nucleoside reverse transcriptase inhibitors (NNRTIs) also keep from infecting cells by interfering with the virus' reverse transcriptase. However, they do it in a different way. The 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.
To enter a host cell, 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. 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 . This is even more effective when entry inhibitor drugs that work by different mechanisms can be used together.
Along with reverse transcriptase and protease, a third enzyme – integrase – is essential for viral replication. Integrase is responsible for inserting viral genomic DNA into the host chromosome. The 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 , including diketo acids, napthyridines, pyranodipyrimidines, and dihydroxythiophenes.
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 life-cycle, viral assembly and maturation offer several potential targets for new therapies.
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