CCR2-RA-[R]

CCR2-RA -[R] can inhibit CCR2 in a non-competitive binding manner, mainly by blocking activation-related conformational changes and the formation of G-protein binding interfaces^[1,2]. For CCR2-RA-[R] the most important residues for binding were found to be the highly conserved tyrosine Y(7.53) and phenylalanine F(8.50) of the NPxxYx(5,6)F motif, as well as V(6.36) at the bottom of TM-VI and K(8.49) in helix-VIII^[3].

CCR2-RA-[R] had IC50 values of 103 nM.Saturation binding experiments yielded a Kp of 5.8 + 0.2 nM with a Bmax of 9.7 + 0.2 pmol/mg.CCR2-RA-[R] clearly showed noncompetitive antagonism for CCR2 with respect to CCL2, as indicated by a decrease in CCL2's efficacy in the presence of increasing concentrations of CCR2RA-[R]^[1].

Focal nerve demyelination increased behavioral reflex responsiveness to mechanical stimuli between postoperative day (POD) 3 and POD28 in both the hindpaw ipsilateral and contralateral to the nerve injury. CCR2 RA-[R] treatment of nerve-injured rats produced stereospecific bilateral reversal of tactile hyperalgesia[4]. CCR2i CCR2-RA-[R] (MCP-1 receptor inhibitor) were administered via intraperitoneal injection. With or without PDX, treatment with CCR2-RA-[R] reduced the number of neutrophils and recruited macrophages, indicating that the basic function of PDX was disappeared after using CCR2 inhibitors(CCR2-RA-[R])^[5]. CCR2 RA-[R] enhances the response to ¨»PD-1 by promoting the counts of progenitor Tex^[6]. Compared to the model group, the fluorescence intensity of spleen was markedly decreased by Pirfenidone and CCR2-RA-[R] Moreover, Compared to the model group, the fluorescence intensity of liver metastasis foci was dramatically reduced by Pirfenidone and CCR2-RA-[R]^[7].

References:
[1]. Zweemer AJ, Nederpelt I,et,al. Multiple binding sites for small-molecule antagonists at the CC chemokine receptor 2. Mol Pharmacol. 2013 Oct;84(4):551-61. doi: 10.1124/mol.113.086850. Epub 2013 Jul 22. PMID: 23877010.
[2]. Zheng Y, Qin L, ,et,al.Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists. Nature. 2016 Dec 15;540(7633):458-461. doi: 10.1038/nature20605. Epub 2016 Dec 7. PMID: 27926736; PMCID: PMC5159191.
[3]. Zweemer AJ, Bunnik J, ,et,al.Discovery and mapping of an intracellular antagonist binding site at the chemokine receptor CCR2. Mol Pharmacol. 2014 Oct;86(4):358-68. doi: 10.1124/mol.114.093328. Epub 2014 Jul 14. PMID: 25024169.
[4]. Bhangoo S, Ren D, ,et,al. Delayed functional expression of neuronal chemokine receptors following focal nerve demyelination in the rat: a mechanism for the development of chronic sensitization of peripheral nociceptors. Mol Pain. 2007 Dec 12;3:38. doi: 10.1186/1744-8069-3-38. PMID: 18076762; PMCID: PMC2228278.
[5]. Ye Y, Zhang HW, et,al. PDX regulates inflammatory cell infiltration via resident macrophage in LPS-induced lung injury. J Cell Mol Med. 2020 Sep;24(18):10604-10614. doi: 10.1111/jcmm.15679. Epub 2020 Jul 31. PMID: 32735065; PMCID: PMC7521295.
[6]. Yihua Xu, Hao Wang, et,al. DFB Suppresses Obesity-Driven CRC Via Restricting Progenitor to Terminally Exhausted T Cell Differentiation, 19 October 2021, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-952538/v1]
[7]. Chen C, Yao X, et,al. Dahuang Zhechong Pill suppresses colorectal cancer liver metastasis via ameliorating exosomal CCL2 primed pre-metastatic niche. J Ethnopharmacol. 2019 Jun 28;238:111878. doi: 10.1016/j.jep.2019.111878. Epub 2019 Apr 13. PMID: 30986521.