The seven-spanning transmembrane G-protein coupled receptor CXCR4, which specifically binds to the chemokine CXCL12, is expressed on many cell types, including various types of tumour cells. CXCR4 plays a crucial role in organ-specific metastasis, directing migration of malignant cells expressing this receptor toward microenvironments where the cognate ligand is secreted. CXCL12 has a direct growth and survival-promoting effect for various cancer cells and enhances moreover tumour angiogenesis by recruiting endothelial progenitor cells to tumours. Drugs which modulate the CXCL12/CXCR4 axis are therefore promising candidates in anti-cancer therapies. CXCR4 is also a coreceptor for human immunodeficiency virus type 1 (HIV-1) X4 virus and, as such, plays an important role in virus entry into target cells. Hence, antiviral agents that bind to CXCR4 are expected to inhibit HIV-1 entry. Here we review the structure, mechanism of action and biological activity of the main CXCR4 antagonists (peptide inhibitors, non-peptide antagonists, neutralizing antibodies, modified analogues of CXCL12) and agonists (CXCL12 peptide analogues) and discuss the CXCL12/CXCR4 axis as an important target in development of anti-tumoral and anti-HIV-1 therapies.
Keywords: CXCR4, CXCL12, antagonist, agonist, analogue, cancer, HIV-1, hematopoietic progenitor mobilization, cognate ligand, angiogenesis, human immunodeficiency virus type 1, peptide inhibitors,, chemokine receptors, G-protein coupled receptor (GPCR), bone marrow, lymph nodes, lung, brain, liver, peptide, Tachypleus tridentatus, Limulus polyphemus, TZ14004, TN14003, TC14012, 4F-benzoyl-TN14003, T-140-Based Cyclic Pentapeptides, Linear T140-Based Oligopeptides, tripeptide mimetics, p-fluorobenzoylated tripeptide mimetics, AMD3100, AMD3100-Based Non-Cyclam Compounds, Dipicolylamine zinc(II)-Based Compounds, HSEFFR-CPC-RFFESH, aberrant hematopoiesi, homodimerization, Epstein-Barr virus-encoded