Tuesday, 19 June 2018

HIV Drugs and their Targets

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.

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