Molecular Interactions of Cyclam and Bicyclam Non-peptide Antagonists with the CXCR4 Chemokine Receptor

Gerlach, Lars Ole; Skerlj, Renato T.; Bridger, Gary; Schwartz, Thue W.

doi:10.1074/jbc.m010429200

Cited by 254 publications

(302 citation statements)

References 28 publications

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279

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“…2). Previous studies showed that the CXCR4 interaction sites of KRH-3955 are different from those of AMD3100 (Gerlach et al, 2001;Murakami et al, 2009;Rosenkilde et al, 2007). Our and previous findings suggest that HIV-1 acquires resistance to CXCR4 antagonists in a competitive way without switching coreceptor usage, which appears different to the mechanisms of resistance to CCR5 antagonists (Kuhmann et al, 2004;Marozsan et al, 2005;Pugach et al, 2007;Trkola et al, 2002;Westby et al, 2007).…”

Section: Discussioncontrasting

confidence: 39%

Increased HIV-1 sensitivity to neutralizing antibodies by mutations in the Env V3-coding region for resistance to CXCR4 antagonists

Hikichi

Yokoyama

Takemura

et al. 2016

Journal of General Virology

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HIV-1 passage in cell culture in the presence of chemokine receptor antagonists can result in selection of viruses with env mutations that confer resistance to these inhibitors. In the present study, we examined the effect of HIV-1 env mutations that confer resistance to CXCR4 antagonists on envelope (Env) sensitivity to neutralizing antibodies (NAbs). Serial passage of CXCR4-tropic HIV-1 NL4-3 in PM1/CCR5 cells under CXCR4 antagonists KRH-3955, AMD3100 and AMD070 yielded two KRH-3955-resistant, one AMD3100-resistant and one AMD070-resistant viruses. These viruses had multiple env mutations including the Env gp120 V3 region. The majority of viruses having these CXCR4 antagonist-resistant Envs showed higher sensitivity to NAbs 447-52D, b12 and 2F5 targeting the V3 region, the gp120 CD4-binding site and the gp41 membrane proximal region, respectively, compared to NL4-3 WT virus. Recombinant NL4-3 viruses with the V3-coding region replaced with those derived from the CXCR4 antagonist-resistant viruses showed increased sensitivity to NAbs b12, 2F5 and 447-52D. Molecular dynamics simulations of Env gp120 outer domains predicted that the V3 mutations increased levels of fluctuations at the tip and stem of the V3 loop. These results indicate that mutations in the V3-coding region that result in loss of viral sensitivity to CXCR4 antagonists increase viral sensitivity to NAbs, providing insights into our understanding of the interplay of viral Env accessibility to chemokine receptors and sensitivity to NAbs.

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Section: Discussioncontrasting

confidence: 39%

Increased HIV-1 sensitivity to neutralizing antibodies by mutations in the Env V3-coding region for resistance to CXCR4 antagonists

Hikichi

Yokoyama

Takemura

et al. 2016

Journal of General Virology

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“…CXCR4(D171A) does have dramatically decreased SDF-1 binding (data not shown), complicating interpretation of the displacement analysis (9). Our molecular modeling provides a spatial rationalization of the involvement of Asp 262 and Glu 288 in AMD3100 binding to the two bicyclam rings that is also consistent with the interaction of the hydrophobic interaction of the phenylenebis(methylene) linker with the contiguous aromatic residues Phe 189 and Tyr 190 .…”

Section: Cxcr4 Inhibitorsmentioning

confidence: 64%

Lipid Bilayer Simulations of CXCR4 with Inverse Agonists and Weak Partial Agonists

Trent

Wang

Murray

et al. 2003

Journal of Biological Chemistry

111

120

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CXCR4 is a G protein-coupled receptor (GPCR) that has multiple critical functions in normal and pathologic physiology that include regulation of the metastatic behavior of mammary carcinoma, and utilization as a coreceptor for infection by T-tropic strains of human immunodeficiency virus-1. Molecular dynamic simulations of the rhodopsin-based homology model of CXCR4 were performed in a solvated lipid bilayer to reproduce the microenvironment of this integral membrane protein.The amino acids in CXCR4 necessary for interaction with an inverse agonist, T140, and a weak partial agonist, AMD3100, identified by alanine scanning mutants, were spatially consistent when computationally docked. Whereas T140 binds residues in extracellular domains and regions of the hydrophobic core proximal to the cell surface, amino acids in the central hydrophobic core are critical to binding of AMD3100. The physical localization of T140 binding to CXCR4 by biochemical analyses corroborated the molecular and computational approaches. The structural basis for the interaction of T140 and AMD3100 with CXCR4 confirms that the mechanisms used by these agents are different. This complementary utilization of molecular, physical, and computation analysis provides a powerful approach to elucidate GPCR conformation.

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“…135 Plerixafor Plerixafor (AMD3100, Genzyme Corporation, Cambridge, MA, USA) is a selective and reversible antagonist of CXCR4 and disrupts its interaction with SDF-1, thereby releasing hematopoietic stem cells into the circulation. [136][137][138] Plerixafor used in conjunction with G-CSF has been shown in a phase 2 study to quickly and predictably enhance the numbers of CD34 þ cells circulating in the peripheral blood. 139 In this study, patients with NHL mobilized more CD34 þ cells per day of apheresis after administration of plerixafor plus G-CSF than after administration of G-CSF alone (median increase of 4.4-fold (range: 1.1-to 54.4-fold)).…”

Section: Novel Agentsmentioning

confidence: 99%

Improving stem cell mobilization strategies: future directions

Bensinger

DiPersio

McCarty

2009

Bone Marrow Transplant

202

209

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Molecular Interactions of Cyclam and Bicyclam Non-peptide Antagonists with the CXCR4 Chemokine Receptor

Cited by 254 publications

References 28 publications

Increased HIV-1 sensitivity to neutralizing antibodies by mutations in the Env V3-coding region for resistance to CXCR4 antagonists

Increased HIV-1 sensitivity to neutralizing antibodies by mutations in the Env V3-coding region for resistance to CXCR4 antagonists

Lipid Bilayer Simulations of CXCR4 with Inverse Agonists and Weak Partial Agonists

Improving stem cell mobilization strategies: future directions

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