A future perspective on the development of chemokine receptor CXCR4 antagonists

Abstract

Background: In the postgenome era, G-protein-coupled receptor families have been recognized as significant drug targets in medicinal chemistry. A specific chemokine receptor, CXCR4, has multiple critical functions in normal physiologies including embryonic development of the cardiovascular, hemopoietic and central nervous systems, and underlies problematic pathologies such as HIV infection, cancer metastasis, leukemia progression and rheumatoid arthritis. Methods and results: A tetradecamer peptide, T140, derived from the horseshoe crab, and its biologically stable derivative, 4F-benzoyl-TN14003, were found to be powerful CXCR4 antagonists that block HIV entry to cells. These peptides have also shown remarkable inhibitory activity against cancer metastasis and progression in a variety of cancers. Slow release administration of 4F-benzoyl-TN14003, for example, was found to significantly reduce pulmonary metastasis of breast cancer cells in severe combined immunodeficient mice. This peptide also shows inhibitory effects against melanoma metastasis and Epstein–Barr virus-associated lymphoproliferation in mice, suppresses the delayed-type hypersensitivity response induced by sheep red blood cells and reduced collagen-induced arthritis in both mouse models of arthritis. Conclusion: T140 analogues have the potential to become promising agents for chemotherapy of AIDS, cancer and rheumatoid arthritis. This review summarizes the development of low molecular weight CXCR4 antagonists based on pharmacophore identification in T140 analogues and also provides an opinion on the future of the development of CXCR4 antagonists.

Keywords::

• AIDS
• cancer metastasis
• chemokine receptor
• CXCR4 antagonist
• FC131
• HIV infection
• leukemia
• rheumatoid arthritis
• T140
• T22

Acknowledgements

The authors acknowledge their collaborators: N Yamamoto (National Institute of Infectious Diseases), H Nakashima (St. Marianna University), H Mitsuya (Kumamoto University), T Hattori (Tohoku University), M Waki (Kyushu University), R Doi (Kyoto University), M Imamura (Kyoto University), Y Tanaka (University of the Ryukyus), A Otaka (The University of Tokushima), I Hamachi (Kyoto University), LJ Bendall (University of Sydney), JO Trent (University of Louisville), SC Peiper (Medical College of Georgia), T Murakami (National Institute of Infectious Diseases), T Mori (Kyoto University), M Takenaga (St. Marianna University), R Igarashi, (St. Marianna University), Z Wang (Medical College of Georgia), JA Burger (Freiburg University), M Burger (Freiburg University), ACW Zannettino (University of Adelaide), E Piovan (University of Padua), JG Cyster (University of California San Francisco), J Zheng (University of Nebraska Medical Center), N Heveker (Universite de Montreal), H Xiong (University of Nebraska Medical Center), M Retz (University of California San Francisco), S Kusano (St. Marianna University), S Terakubo (St. Marianna University), A Ojida (Kyoto University), S Oishi (Kyoto University), S Ueda (Kyoto University), J Komano (National Institute of Infectious Diseases), K Ohba (National Institute of Infectious Diseases), K Hiramatsu (Kyoto University), T Araki (Kyoto University), B Evans (Medical College of Georgia), Y Tanabe (Tokyo Medical and Dental University), A Omagari (Kyoto University), A Esaka (Kyoto University) and N Ohashi (Tokyo Medical and Dental University).

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