CCR5 Antagonist

CCR5 receptor antagonists are a class of small molecules that antagonize the CCR5 receptor. The C-C motif chemokine receptor CCR5 is involved in the process by which HIV, the virus that causes AIDS, enters cells. Hence antagonists of this receptor are entry inhibitors and have potential therapeutic applications in the treatment of HIV infections.The life cycle of the HIV presents potential targets for drug therapy, one of them being the viral entry pathway. The C-C motif chemokine receptors CCR5 and CXCR4 are the main chemokine receptors involved in the HIV entry process. These receptors belong to the seven transmembrane G-protein-coupled receptor (GPCR) family and are predominantly expressed on human T-cells, dendritic cells and macrophages, Langerhans cells.They play an important role as co-receptors that HIV type 1 (HIV-1) uses to attach to cells before viral fusion and entry into host cells.[1] HIV isolates can be divided into R5 and X4 strains. R5 strain is when the virus uses the co-receptor CCR5 and X4 strain is when it uses CXCR4. The location of CCR5 receptors at the cell surface, both large and small molecules have the potential to interfere with the CCR5-viral interaction and inhibit viral entry into human cells.

Mechanism of action HIV enters host cells in the blood by attaching itself to receptors on the surface of the CD4+ cell.[8] Viral entry to the CD4+ cell begins with attachment of the R5 HIV-1 glycoprotein 120 (gp120) to the CD4+ T-cell receptor, which produces a conformational change in gp120 and allows it to bind to CCR5, thereby triggering glycoprotein 41 (gp41) mediated fusion of the viral envelope with the cell membrane and the nucleocapsid enters the host cell. CCR5 co-receptor antagonists prevent HIV-1 from entering and infecting immune cells by blocking CCR5 cell-surface receptor. Small molecule antagonists of CCR5 bind to a hydrophobic pocket formed by the transmembrane helices of the CCR5 receptor. They are thought to interact with the receptor in an allosteric manner locking the receptor in a conformation that prohibits its co-receptor function.

Treatment for HIV

At present treatment for HIV infection involves using a combination of drugs. One type of drug inhibits nucleic acid replication, for example, when AZT is incorporated into DNA by reverse trasncriptase, no additional nucleotides can be added.

A second class of drugs inhibits a protease involved in cleaving large polyproteins into functional segments. When the protease is inhibited, virus particles cannot be produced Use of a combination of drugs directed at different targets reduces the likelihood of the development of resistance by mutation.

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Research is underway to develop new treatments for HIV. Chemicals called chemokines appear to inhibit HIV infection by binding to and blocking the CXCR4 and CCR5 co receptors on the host cells.

A search is in progress to apply such chemicals in HIV treatment,Some individuals who are HIV positive, but did not develop AIDS have a mutation in the CCR5 receptor that makes it defective.

Research is in progress to determine whether disabling the CCR5 receptor might beeffective in controlling AIDS in infected patients.An antiviral factor called CAF is found in CD8 cells.Research is in progress to determine if this substance could be used to block replication of HIV.

There is currently no approved vaccine against HIV infection. One problem is that HIVsurface proteins such as gp120 mutate at a high rate.Scientist may be able to construct a vaccine using an HIV with a defective form of the viral gene nef.

Viruses with the defective nef gene seem to have reduced reproductive capability, allowing the immune system to keep the virus in check.