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Antimicrobial Agents and Chemotherapy, February 2009, p. 631-638, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.00866-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Specific Interactions between the Viral Coreceptor CXCR4 and the Biguanide-Based Compound NB325 Mediate Inhibition of Human Immunodeficiency Virus Type 1 Infection{triangledown}

Nina Thakkar,1 Vanessa Pirrone,1 Shendra Passic,1 Wei Zhu,2 Vladyslav Kholodovych,2 William Welsh,2 Robert F. Rando,3 Mohamed E. Labib,3 Brian Wigdahl,1 and Fred C. Krebs1*

Department of Microbiology and Immunology, and Center for Molecular Therapeutics and Resistance, Center for Sexually Transmitted Disease, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102,1 Robert Wood Johnson Medical School, University of Medicine & Dentistry of New Jersey, Piscataway, New Jersey 08854,2 Novaflux Biosciences, Inc., Princeton, New Jersey 085403

Received 30 June 2008/ Returned for modification 26 August 2008/ Accepted 24 November 2008

The present studies were conducted to better define the mechanism of action of polyethylene hexamethylene biguanide (PEHMB) (designated herein as NB325), which was shown in previous studies to inhibit infection by the human immunodeficiency virus type 1 (HIV-1). Fluorescence-activated flow cytometric analyses of activated human CD4+ T lymphocytes exposed to NB325 demonstrated concentration-dependent reductions in CXCR4 epitope recognition in the absence of altered recognition of selected CD4 or CD3 epitopes. NB325 also inhibited chemotaxis of CD4+ T lymphocytes induced by the CXCR4 ligand CXCL12. However, NB325 did not cause CXCR4 internalization (unlike CXCL12) and did not interfere with CXCL12 binding. Additional flow cytometric analyses using antibodies with distinct specificities for extracellular domains of CXCR4 demonstrated that NB325 specifically interfered with antibody binding to extracellular loop 2 (ECL2). This interaction was confirmed using competitive binding analyses, in which a peptide derived from CXCR4 ECL2 competitively inhibited NB325-mediated reductions in CXCR4 epitope recognition. Collectively, these results demonstrate that the biguanide-based compound NB325 inhibits HIV-1 infection by specifically interacting with the HIV-1 coreceptor CXCR4.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Drexel University College of Medicine, Mail stop 1013-A, 245 N. 15th Street, Philadelphia, PA 19102. Phone: (215) 762-7398. Fax: (215) 762-7784. E-mail: fkrebs{at}drexelmed.edu

{triangledown} Published ahead of print on 1 December 2008.

Antimicrobial Agents and Chemotherapy, February 2009, p. 631-638, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.00866-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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