6 Aptamers for Targeted Therapy
147
to the position of conserved cysteine residues in the protein structure, chemokines
can be divided into four categories: CXC, CC, CX3C, and C [152, 153].
6.4.3.1 CCL2
Human chemokine (C-C motif) ligand (CCLs), also known as monocyte chemoattractant protein (MCPs), belongs to the CC chemokine subfamily, including CCL2/MCP1, CCL8/MCP-2, CCL7/MCP-3, and CCL13/MCP-4 [154]. Stimulations including
cytokine (TNF), oxidative stress, or growth factor induce the production of CCLs
[155]. As the first member of CCLs, CCL2 binds to CCR2 receptors and acts on
mononuclear phagocytes, Th/memory T cells, natural killer cells, and basophils
[156], by which inflammatory process was trigged, including leukocyte recruitment
and adhesion to the inflammatory site [157]. NOX-E36 is a 40 nt polyethylene glycol
L-type RNA aptamer of CCL2, which is generated by Spiegelmer® technology [158–
161]. NOX-E36 specifically inhibited the activity of chemokine CCL2, prevented
leukocytes from combining with endothelial cells, and inhibited leukocyte extravasation to inflammatory lesions [162]. NOX-E36 has undergone clinical trials, and
the evaluation of phase 1 and 2 clinical trials in patients with diabetic kidney patients
shows that NOX-E36 has good safety and tolerance, and shows good efficacy within
at least 12 weeks after termination of therapeutic process [163].
6.4.3.2 CXCL10
IFN-γ inducible protein CXCL10/IP-10 belongs to the ELR-CXC subfamily of CXC
chemokine family, which consists of 77 amino acids, of which four are conserved
cysteine residues [164]. CXCL10 is mainly produced in thymus, spleen, and interstitial lymph nodes. IFN-γ specifically stimulates the release of CXCL10, which
further works by interacting with the corresponding receptor CXCR3 [165]. Because
CXCR3 is expressed on activated T cells, the synthesis of CXCL10 is generally
associated with Th1-mediated inflammatory diseases [166]. The main function of
CXCL10 is to recruit leukocytes to the lesions of inflammation. In addition, it also
has significant functions in the production and functionality of effector T cells.
To date, a series of specific high-affinity aptamers against human and mice
CXCL10/IP-10 have been screened. Among them, two effective aptamers for human
CXCL10 were demonstrated highly antagonistic, and the rest were matched with
human and mice CXCL10 simultaneously. Marro et al. [167] selected an efficient RNA aptamer and modified with 3
-PEG constructing a stable 34 nt RNA
aptamer (K D = ∼1.6 nm). It is speculated that the CXCL10 aptamers may be effective therapeutic agents for inhibiting Th1-mediated inflammatory diseases such as
asthma.
147
to the position of conserved cysteine residues in the protein structure, chemokines
can be divided into four categories: CXC, CC, CX3C, and C [152, 153].
6.4.3.1 CCL2
Human chemokine (C-C motif) ligand (CCLs), also known as monocyte chemoattractant protein (MCPs), belongs to the CC chemokine subfamily, including CCL2/MCP1, CCL8/MCP-2, CCL7/MCP-3, and CCL13/MCP-4 [154]. Stimulations including
cytokine (TNF), oxidative stress, or growth factor induce the production of CCLs
[155]. As the first member of CCLs, CCL2 binds to CCR2 receptors and acts on
mononuclear phagocytes, Th/memory T cells, natural killer cells, and basophils
[156], by which inflammatory process was trigged, including leukocyte recruitment
and adhesion to the inflammatory site [157]. NOX-E36 is a 40 nt polyethylene glycol
L-type RNA aptamer of CCL2, which is generated by Spiegelmer® technology [158–
161]. NOX-E36 specifically inhibited the activity of chemokine CCL2, prevented
leukocytes from combining with endothelial cells, and inhibited leukocyte extravasation to inflammatory lesions [162]. NOX-E36 has undergone clinical trials, and
the evaluation of phase 1 and 2 clinical trials in patients with diabetic kidney patients
shows that NOX-E36 has good safety and tolerance, and shows good efficacy within
at least 12 weeks after termination of therapeutic process [163].
6.4.3.2 CXCL10
IFN-γ inducible protein CXCL10/IP-10 belongs to the ELR-CXC subfamily of CXC
chemokine family, which consists of 77 amino acids, of which four are conserved
cysteine residues [164]. CXCL10 is mainly produced in thymus, spleen, and interstitial lymph nodes. IFN-γ specifically stimulates the release of CXCL10, which
further works by interacting with the corresponding receptor CXCR3 [165]. Because
CXCR3 is expressed on activated T cells, the synthesis of CXCL10 is generally
associated with Th1-mediated inflammatory diseases [166]. The main function of
CXCL10 is to recruit leukocytes to the lesions of inflammation. In addition, it also
has significant functions in the production and functionality of effector T cells.
To date, a series of specific high-affinity aptamers against human and mice
CXCL10/IP-10 have been screened. Among them, two effective aptamers for human
CXCL10 were demonstrated highly antagonistic, and the rest were matched with
human and mice CXCL10 simultaneously. Marro et al. [167] selected an efficient RNA aptamer and modified with 3
-PEG constructing a stable 34 nt RNA
aptamer (K D = ∼1.6 nm). It is speculated that the CXCL10 aptamers may be effective therapeutic agents for inhibiting Th1-mediated inflammatory diseases such as
asthma.