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Journal of Virology, December 2005, p. 15398-15404, Vol. 79, No. 24
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.24.15398-15404.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Unique Ligand Binding Sites on CXCR4 Probed by a Chemical Biology Approach: Implications for the Design of Selective Human Immunodeficiency Virus Type 1 Inhibitors

Won-Tak Choi,¹ Shaomin Tian,¹ Chang-Zhi Dong,¹ Santosh Kumar,¹ Dongxiang Liu,¹ Navid Madani,² Jing An,^1,3 Joseph G. Sodroski,² and Ziwei Huang^1,4*

Departments of Biochemistry,¹ Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801,⁴ Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115,² Raylight Chemokine Pharmaceutical Inc., 10931 N. Torrey Pines Road, La Jolla, California 92037³

Received 24 July 2005/ Accepted 22 September 2005

The chemokine receptor CXCR4 plays an important role as the receptor for the normal physiological function of stromal cell-derived factor 1 (SDF-1) and the coreceptor for the entry of human immunodeficiency virus type 1 (HIV-1) into the cell. In a recent work (S. Tian et al., J. Virol. 79:12667-12673, 2005), we found that many residues throughout CXCR4 transmembrane (TM) and extracellular loop 2 domains are specifically involved in interaction with HIV-1 gp120, as most of these sites did not play a role in either SDF-1 binding or signaling. These results provided direct experimental evidence for the distinct functional sites on CXCR4 for HIV-1 and the normal ligand SDF-1. To further understand the CXCR4-ligand interaction and to develop new CXCR4 inhibitors to block HIV-1 entry, we have recently generated a new family of unnatural chemokines, termed synthetically and modularly modified (SMM) chemokines, derived from the native sequence of SDF-1 or viral macrophage inflammatory protein II (vMIP-II). These SMM chemokines contain various de novo-designed sequence replacements and substitutions by D-amino acids and display more enhanced CXCR4 selectivity, binding affinities, and/or anti-HIV activities than natural chemokines. Using these novel CXCR4-targeting SMM chemokines as receptor probes, we conducted ligand binding site mapping experiments on a panel of site-directed mutants of CXCR4. Here, we provide the first experimental evidence demonstrating that SMM chemokines interact with many residues on CXCR4 TM and extracellular domains that are important for HIV-1 entry, but not SDF-1 binding or signaling. The preferential overlapping in the CXCR4 binding residues of SMM chemokines with HIV-1 over SDF-1 illustrates a mechanism for the potent HIV-1 inhibition by these SMM chemokines. The discovery of distinct functional sites or conformational states influenced by these receptor sites mediating different functions of the natural ligand versus the viral or synthetic ligands has important implications for drug discovery, since the sites shared by SMM chemokines and HIV-1 but not by SDF-1 can be targeted for the development of selective HIV-1 inhibitors devoid of interference with normal SDF-1 function.

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* Corresponding author. Present address: The Burnham Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037. Phone: (858) 713-9928. Fax: (858) 713-9927. E-mail: ziweihuang{at}burnham.org.

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Journal of Virology, December 2005, p. 15398-15404, Vol. 79, No. 24
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.24.15398-15404.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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