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CCR5 Receptor Recombinant Protein Key to Chemokines

CCR5 (C-C chemokine receptor 5) contains 7 transmembrane regions and belongs to G protein-coupled receptor (GPCR). CCR5 is a key CCR highly expressed on CD4+T cells, and its binding ligands include: CCL3 (MIP-α), CCL4 (MIP-β) and CCL5 (RANTES).

CCR5 can mediate leukocyte trafficking and plays an important role in inflammatory response, so CCR5 target protein can be used to verify therapeutic research. It has been used to treat diseases such as multiple sclerosis, rheumatoid arthritis, type 1 diabetes, atherosclerosis, and myocarditis.

CCR5 is Involved in Experimental Intracerebral Hemorrhage (ICH)

CCR5 is widely expressed in the cortex, thalamus, striatum, hippocampus, endothelium and ependyma, mainly in neurons, microglia and astrocytes. Inhibition of CCR5 can promote early recovery of motor function after traumatic brain injury and cerebral ischemia in rodents.

Studies have shown that 22 hours after cerebral artery occlusion in mice, CCR5 protein levels in brain tissue, spinal cord and plasma increased. CCR5 protein is upregulated in the early stage of ICH and reaches a peak after 24 hours. At the same time, CCL5 (CCR5 ligand), PKA-Cα, p-CREB and NLRP1 protein levels all show an upward trend. CCL5, as a ligand of CCR5, is consistent with the trend level of CCR5; the upregulation of PKA-Cα and p-CREB can offset the harmful signals of CCR5 activation and promote the maintenance of homeostasis in the damaged brain.

Maraviroc (MVC) is a selective CCR5 antagonist (CD195 antibody) for the treatment of HIV, which can improve immune-mediated acute and chronic tissue inflammation. MVC can improve the symptoms of ICH and reduce neuronal apoptosis. CREB protein is one of the downstream pathway proteins involved in CCR5 signaling. After HIV infects mouse neurons, CCR5 protein is downregulated and CREB protein levels are increased.

CCR5 is Involved in Experimental Autoimmune Encephalomyelitis

CCL5 can activate T cells through CCR5 signal transduction. In this process, chemokine receptors CCR5 and CXCR4 are aggregated to the immune synapse and transmit costimulatory signals through heteropolymerization. The interaction between CCR5 and CCL5 prompts CD4+ T cells to produce IL-2 related to CCR5 expression through NFAT translocation signals. The production of TNF-α, IL-17 and IFN-γ is not related to CCR5 and may be mediated by other receptors of the ligand.

Studies have shown that fusion proteins that bind three CCR5 ligands can effectively treat experimental autoimmune encephalomyelitis while inhibiting the function of effector T cells. Therefore, the implementation of CCR5-IG-based treatment is more effective than blocking this receptor or using CD195 antibodies.

CCR5 is Involved in AIDS (HIV)

HIV mainly infects CD4+T cells, resulting in a decrease in the number of CD4+ T cells, and ultimately leading to immune system dysfunction. Early treatment of HIV is prone to viremia and systemic infection. In addition, the toxicity or adverse reactions of the drug are more obvious, and the development of CCR5 recombinant antibodies is crucial.

The deletion of 32 base pairs (bp) in the open reading frame of the CCR5 gene (CCR5Δ32) will cause the protein to lose its function. The early stage of HIV infection is mediated by the CCR5 type HIV strain, so CCR5Δ32 homozygous individuals are almost completely immune to HIV infection. When the expression of CCR5 receptors in heterozygous individuals is reduced by two times, the efficiency of HIV infection will also decrease. Therefore, the CCR5 target is a hot target for HIV treatment.

Inserting T4 lysozyme (T4L) into GPCR can enhance the stability and solubility of GPCR protein. The CCR5-T4L mutant was designed, and the soluble recombinant protein was expressed and purified using the Escherichia coli expression system. The antiviral effect of the recombinant protein on different donor THP-1 cell lines, primary human macrophages and peripheral blood mononuclear cells was studied.

Different concentrations of soluble recombinant CCR5-T4L protein have biphasic inhibitory and promoting effects on immunodeficiency virus-1 (HIV-1) infection in THP-1 cell lines, human macrophages and human PBMCs. As a co-receptor of HIV-1, soluble recombinant CCR5-T4L interacts with wild-type CCR5, can downregulate CCR5 on the surface of human macrophages, and interacts with CCL5 to inhibit macrophage migration. Recombinant CCR5-T4L protein can promote HIV-1 infection at low concentrations and inhibit HIV-1 infection at high concentrations. Therefore, CCR5 recombinant antibodies can be used as future anti-HIV-1 therapeutic drugs.

CCR5 is Involved in Vascular Injury

CCL5 is expressed in many vascular systems, and NADPH oxidases (Noxs) are the main components of reactive oxygen species (ROS) in blood vessels.

The expression of Nox1 is induced by CCL5 in a concentration-dependent and time-dependent manner, and has no effect on the expression of Nox2 and Nox4. CCL5 affects the production of ROS and the activation of Erk1/2 and NFkB, leading to increased vascular cell migration, proliferation, and inflammatory markers. Nox1 inhibition can block the effects of CCL5, and maraviroc treatment can reduce Nox1 expression and reduce pathological vascular growth.

Therefore, CCL5 is associated with Nox1 expression in blood vessels, and by participating in the NFkB and Erk1/2 pathways, it causes vascular damage. CCR5 antagonists and Nox1 inhibitors are anti-proliferative compounds that reduce the risk of excessive vascular proliferation.

TekBiotech has been committed to the field of antibodies for many years and has extensive experience in therapeutic antibodies. It can provide you with customized antibody drug services. In addition, TekBiotech also provides customized small molecule modification, antibody expression and purification, affinity determination, antibody sequencing and other services to meet customer needs.

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