CXCR4 as a novel target in immunology: moving away from typical antagonists

Caspar, Birgit; Cocchiara, Pietro; Melet, Armelle; Emelen, Kristof Van; Aa, Annegret Van der; Milligan, Graeme; Herbeuval, Jean-Philippe

doi:10.4155/fdd-2022-0007

Cited by 13 publications

(16 citation statements)

References 70 publications

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“…The closely matched spacings between the side chains of D262 6 58 . and E288 7 39 . residues and the cyclam rings therefore appears be the main binding determinant of AMD3100 and other bicyclam analogues.…”

Section: Resultsmentioning

confidence: 99%

“…Each of the two positively charged cyclam rings of AMD3100 45 is stabilized electrostatically by an acidic side chain pointed toward the center of the ring; the cyclam moiety closer to the extracellular side interacts with D262 6 58 . while the cyclam proximal to the transmembrane core interacts with E288 7 39. .…”

Section: Resultsmentioning

confidence: 99%

“…Density for the chemokine Nterminus (res. [1][2][3][4][5][6][7][8][9][10][11][12] was sufficiently resolved to build side chains (Fig. 1b), whereas the remainder of the ligand was less resolved due to flexibility and only permitted main chain tracing (Extended Data Fig.…”

Section: Structural Basis Of Cxcl12 and Amd3100 Action On Cxcr4mentioning

confidence: 99%

“…Mutations in CXCR4 that result in enhanced and prolonged signaling result in a rare immune disorder called WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome 6 . The significant roles of CXCR4 in health and disease have made the receptor an intensely investigated drug target 7 . The small molecule CXCR4 antagonist AMD3100 (plerixafor), initially developed as an HIV entry inhibitor 8 , was FDA-approved as a hematopoietic stem cell mobilizer for autologous transplantation in patients with Non-Hodgkin’s lymphoma or multiple myeloma 9,10 .…”

Section: Mainmentioning

confidence: 99%

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Structural insights into CXCR4 modulation and oligomerization

Saotome,

McGoldrick,

et al. 2024

Preprint

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Activation of the chemokine receptor CXCR4 by its chemokine ligand CXCL12 regulates diverse cellular processes. CXCR4 also serves as a key target for diseases such as cancer and HIV. Previously reported crystal structures of CXCR4 bound to antagonists revealed the architecture of an inactive, homodimeric receptor. However, many structural aspects of CXCR4 remain poorly understood, including its activation by CXCL12, as well as its assembly into higher-order oligomers. Here, we use cryoelectron microscopy (cryoEM) to investigate various modes of CXCR4 regulation in the presence and absence of Giprotein. CXCL12 activates CXCR4 by inserting its N-terminus deep into the CXCR4 orthosteric pocket. The binding of FDA-approved antagonist AMD3100 is stabilized by electrostatic interactions with acidic residues in the 7 transmembrane helix bundle. A potent antibody blocker, REGN7663, binds across the extracellular face of CXCR4 and inserts its CDR-H3 loop into the orthosteric pocket. Trimeric and tetrameric structures of CXCR4 reveal, to our knowledge, previously undescribed modes of GPCR oligomerization. Remarkably, CXCR4 adopts distinct subunit conformations in trimeric and tetrameric assemblies, highlighting how oligomerization could allosterically regulate chemokine receptor function.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Structural Basis Of Cxcl12 and Amd3100 Action On Cxcr4mentioning

confidence: 99%

Section: Mainmentioning

confidence: 99%

See 2 more Smart Citations

Structural insights into CXCR4 modulation and oligomerization

Saotome,

McGoldrick,

et al. 2024

Preprint

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show abstract

“…In the same vein, we have recently shown that CXCR4 can exist in different conformations at the cell surface, some of which are used by particular HIV-1 strains but not by CXCL12 [ 43 ]. Similarly, some CXCR4 ligands induce different signaling responses compared to CXCL12, presumably owing to different interaction sites in the receptor binding pocket [ 44 ]. These data therefore suggest that it is conceivable to inhibit some functions of CXCR4 while preserving others.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Bis-Imidazoline Derivatives as New CXCR4 Ligands

et al. 2023

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The chemokine receptor CXCR4 and its ligand CXCL12 regulate leukocyte trafficking, homeostasis and functions and are potential therapeutic targets in many diseases such as HIV-1 infection and cancers. Here, we identified new CXCR4 ligands in the CERMN chemical library using a FRET-based high-throughput screening assay. These are bis-imidazoline compounds comprising two imidazole rings linked by an alkyl chain. The molecules displace CXCL12 binding with submicromolar potencies, similarly to AMD3100, the only marketed CXCR4 ligand. They also inhibit anti-CXCR4 mAb 12G5 binding, CXCL12-mediated chemotaxis and HIV-1 infection. Further studies with newly synthesized derivatives pointed out to a role of alkyl chain length on the bis-imidazoline properties, with molecules with an even number of carbons equal to 8, 10 or 12 being the most potent. Interestingly, these differ in the functions of CXCR4 that they influence. Site-directed mutagenesis and molecular docking predict that the alkyl chain folds in such a way that the two imidazole groups become lodged in the transmembrane binding cavity of CXCR4. Results also suggest that the alkyl chain length influences how the imidazole rings positions in the cavity. These results may provide a basis for the design of new CXCR4 antagonists targeting specific functions of the receptor.

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IS4‐FAM, a fluorescent tool to study CXCR4 affinity and competitive antagonism in native cancer cells

Hamshaw,

Cominetti,

Nana‐Akyin

et al. 2024

Pharmacology Res & Perspec

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The ability to accurately measure drug‐target interaction is critical for the discovery of new therapeutics. Classical pharmacological bioassays such as radioligand or fluorescent ligand binding assays can define the affinity or Kd of a ligand for a receptor with the lower the Kd, the stronger the binding and the higher the affinity. However, in many drug discovery laboratories today, the target of interest if often artificially upregulated by means of transfection to modify the host cell's genetic makeup. This then potentially invalidates the assumptions of classical pharmacology affinity calculations as the receptor of interest is no longer at normal physiological densities. The CXCR4 receptor is expressed on many different cancer cell types and is associated with metastasis and poor prognosis. Therefore, the CXCR4 receptor is a desirable target for novel therapeutics. In this study, we explore the applicability of the newly developed fluorescently tagged CXCR4 antagonists, IS4‐FAM as an investigative tool to study CXCR4 affinity and competitive antagonism in native, non‐transfected cancer cells using confocal microscopy and flow cytometry. IS4‐FAM directly labels CXCR4 in several cell lines including high CXCR4 expressing SK‐MEL‐28 (malignant melanoma) and PC3 (metastatic prostate cancer) and lower CXCR4 expressing THP‐1 (acute monocytic leukemia) and was competitive with the established CXCR4 antagonist, AMD3100. This highlights the potential of IS4‐FAM as a pharmacological tool for drug discovery in native cells lines and tissues.

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CXCR4 as a novel target in immunology: moving away from typical antagonists

Cited by 13 publications

References 70 publications

Structural insights into CXCR4 modulation and oligomerization

Structural insights into CXCR4 modulation and oligomerization

Discovery of Bis-Imidazoline Derivatives as New CXCR4 Ligands

IS4‐FAM, a fluorescent tool to study CXCR4 affinity and competitive antagonism in native cancer cells

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