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.

HIV Viral Entry

HIV enters macrophages and CD4+ T cells by the adsorption of glycoproteins on its surface to receptors on the target cell followed by fusion of the viral envelope with the cell membrane and the release of the HIV capsid into the cell.

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Entry to the cell begins through interaction of the trimeric envelope complex (gp160 spike) and both CD4 and a chemokine receptor (generally either CCR5 or CXCR4, but others are known to interact) on the cell surface. gp120 binds to integrin α4β7 activating LFA-1 the central integrin involved in the establishment of virological synapses, which facilitate efficient cell-to-cell spreading of HIV-1. The gp160 spike contains binding domains for both CD4 and chemokine receptors. The first step in fusion involves the high-affinity attachment of the CD4 binding domains of gp120 to CD4. Once gp120 is bound with the CD4 protein, the envelope complex undergoes a structural change, exposing the chemokine binding domains of gp120 and allowing them to interact with the target chemokine receptor. This allows for a more stable two-pronged attachment, which allows the N-terminal fusion peptide gp41 to penetrate the cell membrane. Repeat sequences in gp41, HR1 and HR2 then interact, causing the collapse of the extracellular portion of gp41 into a hairpin. This loop structure brings the virus and cell membranes close together, allowing fusion of the membranes and subsequent entry of the viral capsid.

Once HIV has bound to the target cell, the HIV RNA and various enzymes, including reverse transcriptase, integrase, ribonuclease and protease, are injected into the cell. During the microtubule based transport to the nucleus, the viral single strand RNA genome is transcribed into double strand DNA, which is then integrated into a host chromosome.

HIV can infect dendritic cells (DCs) by this CD4-CCR5 route, but another route using mannose-specific C-type lectin receptors such as DC-SIGN can also be used.DCs are one of the first cells encountered by the virus during sexual transmission. They are currently thought to play an important role by transmitting HIV to T cells once the virus has been captured in the mucosa by DCs.

Cancer Metastasis: CXCR4

CXCR4, also called fusin, is an alpha-chemokine receptor specific for stromal-derived-factor-1 (SDF-1 also called CXCL12), a molecule endowed with potent chemotactic activity for lymphocytes.

Metastasis shares many similarities with leukocyte trafficking. Among those chemokine receptors thought to be involved in hemopoietic cell homing, stromal cell-derived factor-1 and its receptor CXC chemokine receptor-4 (CXCR4) have received considerable attention. Like hemopoietic cell homing, levels of stromal cell-derived factor-1 are high at sites of breast cancer metastasis including lymph node, lung, liver, and the marrow. Moreover, CXCR4 expression is low in normal breast tissues and high in malignant tumors, suggesting that a blockade of CXCR4 might limit tumor metastasis investigating the role of a synthetic antagonist 14-mer peptide (TN14003) in inhibiting metastasis in an animal model. Not only was TN14003 effective in limiting metastasis of breast cancer by inhibiting migration, but it may also prove useful as a diagnostic tool to identify CXCR4 receptor-positive tumor cells in culture and tumors in paraffin-embedded clinical samples.

CXC chemokine receptor 4 (CXCR4) has been shown to play a critical role in chemotaxis and homing, which are key steps in cancer metastasis. There is also increasing evidence that links this receptor to angiogenesis; however, its molecular basis remains elusive. Vascular endothelial growth factor (VEGF), one of the major angiogenic factors, promotes the formation of leaky tumor vasculatures that are the hallmarks of tumor progression. On investigating whether CXCR4 induces the expression of VEGF through the PI3K/Akt pathway. Results showed that CXCR4/CXCL12 induced Akt phosphorylation, which resulted in upregulation of VEGF at both the mRNA and protein levels. Conversely, blocking the activation of Akt signaling led to a decrease in VEGF protein levels; blocking CXCR4/CXCL12 interaction with a CXCR4 antagonist suppressed tumor angiogenesis and growth in vivo. Furthermore, VEGF mRNA levels correlated well with CXCR4 mRNA levels in patient tumor samples. In summary, our study demonstrates that the CXCR4/CXCL12 signaling axis can induce angiogenesis and progression of tumors by increasing expression of VEGF through the activation of PI3K/Akt pathway. Findings suggest that targeting CXCR4 could provide a potential new anti-angiogenic therapy to suppress the formation of both primary and metastatic tumors.

Maraviroc HIV Drug

Maraviroc is a drug used in the treatment of HIV infection.Maraviroc is an entry inhibitor. Specifically, maraviroc blocks the chemokine receptor CCR5 which HIV uses as a co receptor to bind and enter a human helper T cell. Because HIV can also use another co receptor, CXCR4, an HIV tropism test such as a trofile assay must be performed to determine if the drug will be effective.

The first step in HIV1 life cycle is viral attachment to the CD4 T-cell surface, the next step is viral entry which involves a cascade of molecular interactions between the viral envelope glycoprotein and two T-cell surface receptors, a primary receptor and a co-receptor. The GP 120 subunit of the envelope protein first binds the CD4 primary receptor this induces a conformational change in GP 120 that allows the co-receptor binding this Binding triggers conformational changes in the GP 41 subunit leading to insertion of its N-terminal fusion peptide into the host cell's membrane.Fusion results release of the viral genome into the cytoplasm .the co-receptors are the members of the superfamily of G-protein coupled receptors over more than a dozen types of co-receptors have been described .But only two co-receptors such as areas of the CCR5 and CXCR4 are used by all HIV-1 strains.
The co-receptors play a crucial role in HIV disease became evident when the common mutational variant of the CCR5 coding gene known as Delta 32 was discovered in 1996 This CCR5 genetic variant results in the production of nonfunctional CCR5 co receptors .The persons with two normal copies of the CCR5gene predominates in the population and are susceptible to HIV infection.The persons who inherit two copies of the CCR5 delta 32 variant from their parents known as delta 32 homozygotes of non functional CCR5 co receptors are appear to be highly resistant to HIV infection.Delta 32 homozygotes that appears not to be associated with any significant deleterious effects. Delta 32 heterozygotes inherit one copy of the CCR5 delta 32 variant from one parent in the normal form of the CCR5gene from the other parent, Delta 32 heterozygotes can become infected with HIV disease progression is significantly delayed compared to those who have two normal copies of the CCR5 gene. To be effective the co receptor antagonist must be directed at a specific co-receptor CCR5 ,THE co-receptor antagonist for example functions by binding specifically to the CCR5 co receptor molecule, The bound co-receptor is blocked from binding the viral GP 120 subunit which prevents the conformational changes on GP 41 which prevents viral particle entry and HIV particles are unable to enter the T cell cannot infected and cannot replicate. Different HIV strains vary in their ability to use the major co-receptors to achieve entry into the host cell some HIV strains easily use CCR5 co receptor summoning the CX Cr4 for a receptor while other viruses geotropic use both. In HIV-infected individual may have only the CCR5 using virus or the CXCR4 using virus or a mixture of CCR5 using CXCR4 using duo tropic viruses.In the early phase of infection the CCR5 using virus predominates in most patients in the late phase of infection HIV strains capable of using CXCR4 recptoe. Unlike reverse transcripase or protease inhibitors which went inside the infected cell to receptor ,Antagonists function on the outside of the host cell,The co-receptor antagonists are therefore classified as entry inhibitors. the mechanism of action of co-receptor antagonists differs from other antiretroviral in a very important way rather than binding to viral proteins this new class prevents viral replication by binding to human cells such as T cells and macrophages this unique mechanism has potential clinical advantages.