Screening and characterization of cyclic pentapeptide CXCR4 antagonists/inverse agonists using a pheromone responsive reporter gene in Saccharomyces cerevisiae: Utility of G protein coupled receptor constitutively active mutants
CXCR4 is a chemokine receptor that belongs to the GPCR superfamily. It specifically transduces the signal of one CXC chemokine ligand, stromal cell derived factor 1 [1, 2], which has been designated CXCL12 in the current nomenclature assigned to members of the chemoattractant cytokine gene family . This GPCR-ligand pair plays a critical role in programming the directed migration of multiple cell types during embryologic development, including neural, endothelial, and hematopoietic progenitors, as well as primordial germ cells . Mice rendered nullizygous for either CXCR4 or CXCL12 by gene targeting die in utero with incomplete formation of the cerebellum, vascular system and the medullary hematopoietic compartment –. During adult life, CXCL12 is a chemoattractant for multiple subsets of leukocyte and exposure to CXCR4 antagonists results in mobilization of (hematopoietic) stem cells . Rare individuals carrying a mutation that results in loss of the normal cytoplasmic tail, either by truncation or translational frame shift, which precludes desensitization following activation have a dominant syndrome characterized by warts, hypogammaglobulinemia, infections, and myelokathexis (retention of myeloid cells in the bone marrow) .
KeywordsPrimordial Germ Cell Inverse Agonist Galactosidase Activity CXCR4 Antagonist Biologic Potency
Unable to display preview. Download preview PDF.
- 14.Hendrix CW, Collier AC Lederman MM, Schols D, Pollard RB, Brown S, Jackson JB, Coombs RW, Glesby MJ, Flexner CW et al; AMD3100 HIV Study Group (2004) Safety, pharmacokinetics, and antiviral activity of AMD3100, a selective CXCR4 receptor inhibitor, in HIV-1 infection. J Acquir Immune Defic Syndr 37: 1253–1262PubMedCrossRefGoogle Scholar
- 21.Castellone MD, Guarino V, De Falco V, Carlomagno F, Basolo F, Faviana P, Kruhoffer M, Orntoft T, Russell JP, Rothstein JL et al (2004) Functional expression of the CXCR4 chemokine receptor is induced by RET/PTC oncogenes and is a common event in human papillary thyroid carcinomas. Oncogene 23: 5958–5967PubMedCrossRefGoogle Scholar
- 25.Jankowski K, Kucia M, Wysoczynski M, Reca R, Zhao D, Trzyna E, Trent J, Peiper S, Zembala M, Ratajczak J et al (2003) Both hepatocyte growth factor (HGF) and stromal-derived factor-1 regulate the metastatic behavior of human rhabdomyosarcoma cells, but only HGF enhances their resistance to radiochemotherapy. Cancer Res 63: 7926–7935PubMedGoogle Scholar
- 27.Burger JA, Spoo A, Dwenger A, Burger M, Behringer D (2003) CXCR4 chemokine receptors (CD184) and alpha4beta1 integrins mediate spontaneous migration of human CD34+ progenitors and acute myeloid leukaemia cells beneath marrow stromal cells (pseudoemperipolesis). Br J Haematol 122: 579–589PubMedCrossRefGoogle Scholar
- 29.Ichiyama K, Yokoyama-Kumakura S, Tanaka Y, Tanaka R, Hirose K, Bannai K, Edamatsu T, Yanaka M, Niitani Y, Miyano-Kurosaki N et al (2003) A duodenally absorbable CXC chemokine receptor 4 antagonist, KRH-1636, exhibits a potent and selective anti-HIV-1 activity. Proc Natl Acad Sci USA 100: 4185–4190PubMedCrossRefGoogle Scholar
- 30.Fujii N, Oishi S, Hiramatsu K, Araki T, Ueda S, Tamamura H, Otaka A, Kusano S, Terakubo S, Nakashima H et al (2003) Molecular-size reduction of a potent CXCR4-chemokine antagonist using orthogonal combination of conformation-and sequence-based libraries. Angew Chem Int Ed Engl 42: 3251–3253PubMedCrossRefGoogle Scholar
- 31.Zhang WB, Navenot JM, Haribabu B, Tamamura H, Hiramatu K, Omagari A, Pei G, Manfredi JP, Fujii N, Broach JR, Peiper SC (2002) A point mutation that confers constitutive activity to CXCR4 reveals that T140 is an inverse agonist and that AMD3100 and ALX40-4C are weak partial agonists. J Biol Chem 277: 24515–24521PubMedCrossRefGoogle Scholar