Different contributions of chemokine N‐terminal features attest to a different ligand binding mode and a bias towards activation of ACKR3/CXCR7 compared with CXCR4 and CXCR3

Szpakowska, Martyna; Nevins, Amanda M.; Meyrath, Max; Rhainds, David; D’huys, Thomas; Guité-Vinet, François; Dupuis, Nadine; Gauthier, Pierre-Arnaud; Counson, Manuel; Kleist, Andrew B.; St-Onge, Geneviève; Hanson, Julien; Schols, Dominique; Volkman, Brian F.; Heveker, Nikolaus; Chevigné, Andy

doi:10.1111/bph.14132

Cited by 55 publications

(87 citation statements)

References 78 publications

(135 reference statements)

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“…Moreover, the authors suggest that arrestin binding to ACKR3 is not required for chemokine scavenging . The finding somewhat contrasts other observations where it was shown that CXCL11 and CXCL12 binding to ACKR3 enhances arrestin recruitment …”

Section: Introductioncontrasting

confidence: 57%

“…In their study, the authors used peptides derived from the N‐termini of CXCL11 and CXCL12, to show different binding and activation potencies depending of amino acid substitutions. However, contrarily to our chimeric chemokine, which has comparable affinity to ACKR3 as the natural ligands, the peptides have a markedly lower affinity (100–2000‐fold) for ACKR3 . It is conceivable and in line with radiolytic footprinting analysis of CXCL12:ACKR3 complexes, that both the N‐terminus and the body constitute together the high affinity binding to ACKR3 …”

Section: Discussionmentioning

confidence: 80%

“…We exchanged the N‐terminus of CXCL12 with the corresponding amino acids derived from CXCL11, driven by the notion that CXCR4 is particularly sensitive to modifications of the N‐terminus of CXCL12 . A recent study suggests that chemokine binding and activation of ACKR3 differs significantly from that of the typical receptors CXCR3 and CXCR4 . In their study, the authors used peptides derived from the N‐termini of CXCL11 and CXCL12, to show different binding and activation potencies depending of amino acid substitutions.…”

Section: Discussionmentioning

confidence: 99%

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Characterization of a chimeric chemokine as a specific ligand for ACKR3

Ameti

Melgrati

Radice

et al. 2018

Journal of Leukocyte Biology

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and CXCL11 bind to the canonical receptors CXCR4 and CXCR3, respectively. Here, we present the engineering of a chemokine-like chimera, which selectively binds to ACKR3. The addition of a ybbR13 tag at the C-terminus allows site specific enzymatic labeling with a plethora of fluorescent dyes. The chimera is composed of the N-terminus of CXCL11 and the main body and C-terminus of CXCL12 and selectively interacts with ACKR3 with high affinity, while not interfering with binding of CXCL11 and CXCL12 to their cognate receptors. We further provide evidence that the chimera can be used to study ACKR3 function in vivo.

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Section: Introductioncontrasting

confidence: 57%

Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

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Characterization of a chimeric chemokine as a specific ligand for ACKR3

Ameti

Melgrati

Radice

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: 39%

“…These studies led to the identification of a 21‐mer peptide derived from the N‐terminus of vCCL2 (vCCL2 (1–21) ) that displayed only modest CXCR4‐binding affinity and antiviral properties. We have recently identified vCCL2 and peptides derived from its N‐terminus as novel agonists of ACKR3 . In the current study, we exploited the high throughput screening capacity of the phage display technology to select Mimokines, vCCL2 (1–21) peptide‐based variants with enhanced CXCR4‐binding properties and selectivity.…”

Section: Introductionmentioning

confidence: 99%

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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