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Ccr5 receptor antagonist

The meaning of «ccr5 receptor 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. CCR5 and CXCR4 are the main 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.[1] 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.[2] 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.[3]

Since the discovery of HIV in the 1980s, remarkable progress has been made in the development of novel antiviral drugs.[2] The trigger for the discovery of the CCR5 antagonists was the observation that a small percentage of high-risk populations showed either resistance or delayed development of the disease. This population was found to have a mutation (CCR5-Δ32) in the gene that codes for the CCR5 receptor which results in almost complete resistance against HIV-1 infection and scientists then discovered the key role of the cell surface receptors CCR5 and CXCR4 in successful viral fusion and infection.[4] In 1996, it was demonstrated that CCR5 serves as a co-receptor for the most commonly transmitted HIV-1 strains, R5. This type of virus is predominant during the early stages of infection and remains the dominant form in over 50% of late stage HIV-1 infected patients,[5][6] however R5 strains can eventually evolve into X4 as the disease progresses.[2] This information led to the development of a new class of HIV drugs called CCR5 antagonists.[7]

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 (Figure 1).[8][9] CCR5 co-receptor antagonists prevent HIV-1 from entering and infecting immune cells by blocking CCR5 cell-surface receptor.[10] Small molecule antagonists of CCR5 bind to a hydrophobic pocket formed by the transmembrane helices of the CCR5 receptor.[11] They are thought to interact with the receptor in an allosteric manner locking the receptor in a conformation that prohibits its co-receptor function.[12]

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