Inhibition of HIV Infection by Bicyclams, Highly Potent and Specific CXCR4 Antagonists
- Rega Institute for Medical Research, Department of Microbiology and Immunology, Division of Virology and Chemotherapy, Katholieke Universiteit, Leuven, Leuven, Belgium
Abstract
The bicyclams represent a new entity of low-molecular weight molecules that inhibit human immunodeficiency virus (HIV) infection through a specific blockade of CXCR4 (fusin), the receptor for the CXC chemokine SDF-1 (soluble-derived factor), which is also used as coreceptor by T-lymphotropic HIV strains to enter their target cells. The bicyclam AMD3100 or 1,1′-[1,4-phenylenebis(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane octahydrochloride dihydrate, is able to block the CXCR4 receptor and to inhibit HIV replication at nanomolar concentrations while not being toxic to the host cells at 100,000-fold higher concentrations. It is the most specific and most potent CXCR4 antagonist that has been described to date.
Footnotes
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Send reprint requests to: Prof. Dr. Erik De Clercq, Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium. E-mail: erik.declercq{at}rega.kuleuven.ac.be
- Abbreviations:
- RANTES
- regulated upon activation normal T cell expressed and secreted
- SIV
- simian immunodeficiency virus
- mAb
- monoclonal antibody
- PBMC
- peripheral blood mononuclear cell
- AZT
- azidothymidine (zidovudine)
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- Received December 29, 1999.
- Accepted February 4, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
