Introduction
TC 14012 is a serum-stable derivative of the peptidomimetic T140, which is a cyclic peptide with the structure of [Cit6, D-Cit8]-T140 and contains the C-terminal amide. T140 is a typically amphiphilic peptide containing basic residues (5 Arg, 1 Lys and 1 D-Lys residues) and hydrophobic residues, exhibiting total +7 positive charges. Research has shown that there is an apparent correlation between the number of the net positive charges and anti-HIV activity or cytotoxicity, and that reduction of total positive charges results in even less cytotoxicity whereas extreme reduction cuases a significant decrease in anti-HIV activity, so the strategy of reduction of total positive charges by substitution for basic residues (Arg and Lys) with nonbasic polar amino acids, such as L-citrulline (Cit), is useful for developing effective analogues possessing high activity and low cytotoxicity.
Biological Activity
TC 14012 strongly inhibits the T-cell line-tropic HIV-1 (X4-HIV-1) infection through its specific binding to a chemokine receptor, CXCR4 (C-X-C chemokine receptor type 4). CXCR4 is a major coreceptor (second receptor) for the entry of X4-HIV-1 into T-cells. TC14012 showed the highest level of anti-defense activity and antagonism of target cell entry by X4-HIV-1 among all the CXCR4 antagonists through the structure-activity relationship study on tachyplesins and polyphemusins.
Function
TC 14012 is not only a CXCR4 antagonist, but also participates in CXCR7, albeit with much lower potency. CXCR7 (also known as ACKR3) is a receptor for the chemokines CXCL11 and CXCL12, which in turn also bind CXCR3, and CXCR4, respectively. As an antagonist of CXCR4, it blocks CXCR4-mediated HIV infection with an IC50 value of 19.3 nM. In addition, TC 14012 (100 μg/ml) inhibits CXCL12-induced phosphorylation of p42/44 MAPK and STAT3 in B cells from patients with chronic lymphocytic leukemia. This peptidomimetic is C-terminally amidated, resulting in high stability in serum. TC 14012 also activates CXCR7 (EC50= 350 nM), resulting in the recruitment of β-arrestin and Erk½ phosphorylation.
References:
1. Stephanie Gravel, Camille Malouf, Philip E. Boulais, Yamina A. Berchiche, Shinya Oishi, Nobutaka Fujii, Richard Leduc, Daniel Sinnett, Nikolaus Heveker. The Peptidomimetic CXCR4Antagonist TC14012 Recruits β-Arrestin to CXCR7-ROLES OF RECEPTOR DOMAINS. Journal of Biological Chemistry, 2010, 285 (49), 37939-37943.
2. Hirokazu Tamamura,a, Akane Omagari, Kenichi Hiramatsu, Kazuyo Gotoh, Taisei Kanamoto, Younong Xu, Eiichi Kodama, Masao Matsuoka, Toshio Hattori, Naoki Yamamoto, Hideki Nakashima, Akira Otakaa, Nobutaka Fujii. Development of Specific CXCR4 Inhibitors Possessing High Selectivity Indexes as Well as Complete Stability in Serum Based on an Anti-HIV Peptide T140. Bioorganic & Medicinal Chemistry Letters, 2001, 11 (14), 1897-1902.
3. Hirokazu Tamamura, Kenichi Hiramatsu, Shuichi Kusano, Shigemi Terakubo, Naoki Yamamoto, John O. Trent, Zixuan Wang, Stephen C. Peiper, Hideki Nakashima, Akira Otaka and Nobutaka Fujii. Synthesis of potent CXCR4 inhibitors possessing low cytotoxicity and improved biostability based on T140 derivatives. Org. Biomol. Chem., 2013, 1, 3656-3662.
