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J. Biol. Chem., Vol. 276, Issue 17, 14153-14160, April 27, 2001
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From the The non-peptide CXCR4 receptor antagonist
AMD3100, which is a potent blocker of human immunodeficiency virus cell
entry, is a symmetrical bicyclam composed of two identical
1,4,8,11-tetraazacyclotetradecane (cyclam) moieties connected by a
relatively rigid phenylenebismethylene linker. Based on the known
strong propensity of the cyclam moiety to bind carboxylic acid groups,
receptor mutagenesis identified Asp171 and
Asp262, located in transmembrane domain (TM) IV and TM-VI,
respectively, at each end of the main ligand-binding crevice of the
CXCR4 receptor, as being essential for the ability of AMD3100 to block
the binding of the chemokine ligand stromal cell-derived factor
(SDF)-1
Molecular Interactions of Cyclam and Bicyclam Non-peptide
Antagonists with the CXCR4 Chemokine Receptor*
,¶
Laboratory for Molecular Pharmacology,
University of Copenhagen, Panum Institute, DK-2200 Copenhagen,
Denmark, § AnorMED Incorporated, Langley, British
Columbia, Canada V2Y 1N5, and ¶ 7TM Pharmaceuticals
A/S, Rønnegade 2, DK-2100 Copenhagen, Denmark
as well as the binding of the receptor antibody 12G5. The
free cyclam moiety had no effect on 12G5 binding, but blocked SDF-1
binding with an affinity of 3 µM through interaction with
Asp171. The effect on SDF-1 binding of a series of
bicyclam analogs with variable chemical linkers was found to rely
either only on Asp171, i.e. the bicyclams acted
as the isolated cyclam, or on both Asp171 and
Asp262, i.e. they acted as AMD3100, depending
on the length and the chemical nature of the linker between the two
cyclam moieties. A positive correlation was found between the
dependence of these compounds on Asp262 for binding and
their potency as anti-human immunodeficiency virus agents. It is
concluded that AMD3100 acts on the CXCR4 receptor through binding to
Asp171 in TM-IV and Asp262 in TM-VI with each
of its cyclam moieties, and it is suggested that part of its function
is associated with a conformational constraint imposed upon the
receptor by the connecting phenylenebismethylene linker.
*
This work was supported by grants from the Danish Medical
Research Council and the 7TM Biotech Competence Center.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Lab. for Molecular
Pharmacology, Panum Institute 18.6.12, Blegdamsvej 3, DK-2200 Copenhagen, Denmark. Tel.: 45-3532-7603; Fax: 45-3535-2995; E-mail: schwartz@molpharm.dk.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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