Inhibition of human immunodeficiency virus replication by a dual CCR5/CXCR4 antagonist.

Abstract

Here we report that the N-pyridinylmethyl cyclam analog AMD3451 has antiviral activity against a wide variety of R5, R5/X4, and X4 strains of human immunodeficiency virus type 1 (HIV-1) and HIV-2 (50% inhibitory concentration [IC(50)] ranging from 1.2 to 26.5 microM) in various T-cell lines, CCR5- or CXCR4-transfected cells, peripheral blood mononuclear cells (PBMCs), and monocytes/macrophages. AMD3451 also inhibited R5, R5/X4, and X4 HIV-1 primary clinical isolates in PBMCs (IC(50), 1.8 to 7.3 microM). A PCR-based viral entry assay revealed that AMD3451 blocks R5 and X4 HIV-1 infection at the virus entry stage. AMD3451 dose-dependently inhibited the intracellular Ca(2+) signaling induced by the CXCR4 ligand CXCL12 in T-lymphocytic cells and in CXCR4-transfected cells, as well as the Ca(2+) flux induced by the CCR5 ligands CCL5, CCL3, and CCL4 in CCR5-transfected cells. The compound did not interfere with chemokine-induced Ca(2+) signaling through CCR1, CCR2, CCR3, CCR4, CCR6, CCR9, or CXCR3 and did not induce intracellular Ca(2+) signaling by itself at concentrations up to 400 microM. In freshly isolated monocytes, AMD3451 inhibited the Ca(2+) flux induced by CXCL12 and CCL4 but not that induced by CCL2, CCL3, CCL5, and CCL7. The CXCL12- and CCL3-induced chemotaxis was also dose-dependently inhibited by AMD3451. Furthermore, AMD3451 inhibited CXCL12- and CCL3L1-induced endocytosis in CXCR4- and CCR5-transfected cells. AMD3451, in contrast to the specific CXCR4 antagonist AMD3100, did not inhibit but enhanced the binding of several anti-CXCR4 monoclonal antibodies (such as clone 12G5) at the cell surface, pointing to a different interaction with CXCR4. AMD3451 is the first low-molecular-weight anti-HIV agent with selective HIV coreceptor, CCR5 and CXCR4, interaction.

• Authors: Katrien Princen, Sigrid Hatse, Kurt Vermeire, Stefano Aquaro, Erik De Clercq, Lars-Ole Gerlach, Mette Rosenkilde, Thue W Schwartz, Renato Skerlj, Gary Bridger, Dominique Schols
• Journal: Journal of virology (J Virol) Vol. 78 Issue 23 Pg. 12996-3006 (Dec 2004) ISSN: 0022-538X [Print] United States
• PMID: 15542651 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-((2,6-dichloropyridin-4-yl)methyl)-1,4,8,11-tetrazacyclotetradecane
• Anti-HIV Agents
• Antibodies, Monoclonal
• CCL3L1 protein, human
• CCR5 Receptor Antagonists
• CXCL12 protein, human
• Chemokine CXCL12
• Chemokines, CC
• Chemokines, CXC
• Heterocyclic Compounds
• Pyridines
• Receptors, CXCR4
• Calcium

Topics

• Anti-HIV Agents (pharmacology)
• Antibodies, Monoclonal (immunology)
• CCR5 Receptor Antagonists
• Calcium (metabolism)
• Chemokine CXCL12
• Chemokines, CC (antagonists & inhibitors)
• Chemokines, CXC (antagonists & inhibitors)
• Chemotaxis (drug effects)
• HIV (drug effects, physiology)
• Heterocyclic Compounds (pharmacology)
• Humans
• Pyridines (pharmacology)
• Receptors, CXCR4 (antagonists & inhibitors)
• Virus Replication (drug effects)