Bivalent Ligands Targeting Chemokine Receptor Dimerization: Molecular Design and Functional Studies

Arnatt, Christopher K.; Zhang, Yan

doi:10.2174/1568026614666140827144752

Cited by 18 publications

(15 citation statements)

References 73 publications

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“…More data are nonetheless required to determine whether there are common residues and/or structural determinants involved in chemokine receptor dimerization, if each receptor bears an individual dimerization signature or even if the residues involved in homodimers are the same that those forming heterodimers. In addition to the CKR themselves, studies that target dimerization with bivalent ligands reinforce the idea that receptor dimerization is essential to understand chemokine biology …”

Section: Chemokine Receptor Dimerization/oligomerization: a Potentialmentioning

confidence: 95%

“…In addition to the CKR themselves, studies that target dimerization with bivalent ligands reinforce the idea that receptor dimerization is essential to understand chemokine biology. 67 Many authors [68][69][70][71][72][73][74][75] have shown the impact of chemokine receptor complexes (dimers/oligomers) on chemokine functions (Table 1).…”

Section: Chemokine Receptor Dimerization/oligomerization: a Potentialmentioning

confidence: 99%

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Remodeling our concept of chemokine receptor function: From monomers to oligomers

Martínez-Muñoz

Villares

Rodrı́guez-Fernández

et al. 2018

Journal of Leukocyte Biology

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The chemokines direct leukocyte recruitment in both homeostatic and inflammatory conditions, and are therefore critical for immune reactions. By binding to members of the class A G protein-coupled receptors, the chemokines play an essential role in numerous physiological and pathological processes. In the last quarter century, the field has accumulated much information regarding the implications of these molecules in different immune processes, as well as mechanistic insight into the signaling events activated through their binding to their receptors. Here, we will focus on chemokine receptors and how new methodological approaches have underscored the role of their conformations in chemokine functions. Advances in biophysical-based techniques show that chemokines and their receptors act in very complex networks and therefore should not be considered isolated entities. In this regard, the chemokine receptors can form homo- and heterodimers as well as oligomers at the cell surface. These findings are changing our view as to how chemokines influence cell biology, identify partners that regulate chemokine function, and open new avenues for therapeutic intervention.

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Section: Chemokine Receptor Dimerization/oligomerization: a Potentialmentioning

confidence: 95%

Section: Chemokine Receptor Dimerization/oligomerization: a Potentialmentioning

confidence: 99%

Remodeling our concept of chemokine receptor function: From monomers to oligomers

Martínez-Muñoz

Villares

Rodrı́guez-Fernández

et al. 2018

Journal of Leukocyte Biology

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“…Improvement of chemokine‐derived short peptide affinity and potency by dimerization via a disulfide bridge at the first cysteine residues has previously been reported and suggested to be due, at least in part, to a mimicry effect of the first disulfide bridge present in the parental chemokines . Surprisingly, in the current study, dimerization of Mimokine SR (D) with C terminal cysteine or lysine linkers enhanced to the same extent the peptide interaction with CXCR4, suggesting that other effects might also be involved.…”

Section: Discussionmentioning

confidence: 83%

Development of Mimokines, chemokine N terminus-based CXCR4 inhibitors optimized by phage display and rational design

Fiévez

Szpakowska

Mosbah

et al. 2018

Journal of Leukocyte Biology

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The chemokine receptor CXCR4 (C-X-C chemokine receptor type 4 also known as fusin or CD184 (cluster of differentiation 184)) is implicated in various biological and pathological processes of the hematopoietic and immune systems. CXCR4 is also one of the major coreceptors for HIV-1 entry into target cells and is overexpressed in many cancers, supporting cell survival, proliferation, and migration. CXCR4 is thus an extremely relevant drug target. Among the different strategies to block CXCR4, chemokine-derived peptide inhibitors hold great therapeutic potential. In this study, we used the N-terminus of vCCL2/vMIPII, a viral CXCR4 antagonist chemokine, as a scaffold motif to engineer and select CXCR4 peptide inhibitors, called Mimokines, which imitate the chemokine-binding mode but display an enhanced receptor affinity, antiviral properties, and receptor selectivity. We first engineered a Mimokine phage displayed library based on the first 21 residues of vCCL2, in which cysteine 11 and 12 were fully randomized and screened it against purified CXCR4 stabilized in liposomes. We identified Mimokines displaying up to 4-fold higher affinity for CXCR4 when compared to the reference peptide and fully protected MT-4 cells against HIV-1 infection. These selected Mimokines were then subjected to dimerization, D-amino acid, and aza-β3-amino acid substitution to further enhance their potency and selectivity. Optimized Mimokines exhibited up to 120-fold enhanced CXCR4 binding (range of 20 nM) and more than 200-fold improved antiviral properties (≤ 1 μM) compared to the parental Mimokines. Interestingly, these optimized Mimokines also showed up to 25-fold weaker affinity for ACKR3/CXCR7 and may therefore serve as lead compounds for further development of more selective CXCR4 peptide inhibitors and probes.

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“…26 The first bivalent ligand (designated as compound 1b , Figure 1) was designed with an overall length of 21 atoms based upon previous bivalent ligand reports involving the MOR, 23 along with two control compounds with the same length of spacer (compound 2b for monovalent control attaching maraviroc, compound 3b for monovalent control attaching naltrexone). In order to study how linker length affects activity, the overall length was decreased or increased by two atoms in compounds 1a or 1c respectively.…”

Section: Resultsmentioning

confidence: 99%

Exploration of bivalent ligands targeting putative mu opioid receptor and chemokine receptor CCR5 dimerization

Arnatt

Falls

Yuan

et al. 2016

Bioorganic & Medicinal Chemistry

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Modern antiretroviral therapies have provided HIV-1 infected patients longer lifespans and better quality of life. However, several neurological complications are now being seen in these patients due to HIV-1 associated injury of neurons by infected microglia and astrocytes. In addition, these effects can be further exacerbated with opiate use and abuse. One possible mechanism for such potentiation effects of opiates is the interaction of the mu opioid receptor (MOR) with the chemokine receptor CCR5 (CCR5), a known HIV-1 co-receptor, to form MOR-CCR5 heterodimer. In an attempt to understand this putative interaction and its relevance to neuroAIDS, we designed and synthesized a series of bivalent ligands targeting the putative CCR5-MOR heterodimer. To understand how these bivalent ligands may interact with the heterodimer, biological studies including calcium mobilization inhibition, binding affinity, HIV-1 invasion, and cell fusion assays were applied. In particular, HIV-1 infection assays using human peripheral blood mononuclear cells, macrophages, and astrocytes revealed a notable synergy in activity for one particular bivalent ligand. Further, a molecular model of the putative CCR5-MOR heterodimer was constructed, docked with the bivalent ligand, and molecular dynamics simulations of the complex was performed in a membrane-water system to help understand the biological observation.

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Bivalent Ligands Targeting Chemokine Receptor Dimerization: Molecular Design and Functional Studies

Cited by 18 publications

References 73 publications

Remodeling our concept of chemokine receptor function: From monomers to oligomers

Remodeling our concept of chemokine receptor function: From monomers to oligomers

Development of Mimokines, chemokine N terminus-based CXCR4 inhibitors optimized by phage display and rational design

Exploration of bivalent ligands targeting putative mu opioid receptor and chemokine receptor CCR5 dimerization

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