Inhibition of HIV Fusion by Small Molecule Agonists through Efficacy-Engineering of CXCR4

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Inhibition of HIV Fusion by Small Molecule Agonists through Efficacy-Engineering of CXCR4. / Berg, Christian; Daugvilaite, Viktorija; Steen, Anne; Jørgensen, Astrid Sissel; Våbenø, Jon; Rosenkilde, Mette Marie.

In: ACS chemical biology, Vol. 13, No. 4, 20.04.2018, p. 881-886.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Berg, C, Daugvilaite, V, Steen, A, Jørgensen, AS, Våbenø, J & Rosenkilde, MM 2018, 'Inhibition of HIV Fusion by Small Molecule Agonists through Efficacy-Engineering of CXCR4', ACS chemical biology, vol. 13, no. 4, pp. 881-886. https://doi.org/10.1021/acschembio.8b00061

APA

Berg, C., Daugvilaite, V., Steen, A., Jørgensen, A. S., Våbenø, J., & Rosenkilde, M. M. (2018). Inhibition of HIV Fusion by Small Molecule Agonists through Efficacy-Engineering of CXCR4. ACS chemical biology, 13(4), 881-886. https://doi.org/10.1021/acschembio.8b00061

Vancouver

Berg C, Daugvilaite V, Steen A, Jørgensen AS, Våbenø J, Rosenkilde MM. Inhibition of HIV Fusion by Small Molecule Agonists through Efficacy-Engineering of CXCR4. ACS chemical biology. 2018 Apr 20;13(4):881-886. https://doi.org/10.1021/acschembio.8b00061

Author

Berg, Christian ; Daugvilaite, Viktorija ; Steen, Anne ; Jørgensen, Astrid Sissel ; Våbenø, Jon ; Rosenkilde, Mette Marie. / Inhibition of HIV Fusion by Small Molecule Agonists through Efficacy-Engineering of CXCR4. In: ACS chemical biology. 2018 ; Vol. 13, No. 4. pp. 881-886.

Bibtex

@article{e0343a6c785f47009f21bf036bd4a0d7,
title = "Inhibition of HIV Fusion by Small Molecule Agonists through Efficacy-Engineering of CXCR4",
abstract = "CXC chemokine receptor 4 (CXCR4) is involved in multiple physiological and pathological processes, notably as a coreceptor for human immunodeficiency virus (HIV) cell entry. Its broad expression pattern and vital biological importance make CXCR4 a troublesome drug target, as disruption of the interaction with its endogenous ligand, CXC chemokine ligand 12 (CXCL12), has severe consequences. In fact, only one CXCR4 drug, the bicyclam antagonist and HIV entry inhibitor AMD3100 (Plerixafor/Mozobil), has been approved for clinical use, however only for stem cell mobilization-a consequence of CXCR4 antagonism. Here, we report the engineering of an efficacy switch mutation in CXCR4-F292A7.43 in the middle of transmembrane helix 7-that converted the antagonists AMD3100 and AMD11070 into partial agonists. As agonists on F292A CXCR4, AMD3100 and AMD11070 were less disruptive to CXCR4 signaling while they remained efficient inhibitors of HIV fusion. This demonstrates that small molecule CXCR4 agonists can have a therapeutic potential as HIV entry inhibitors.",
author = "Christian Berg and Viktorija Daugvilaite and Anne Steen and J{\o}rgensen, {Astrid Sissel} and Jon V{\aa}ben{\o} and Rosenkilde, {Mette Marie}",
year = "2018",
month = apr,
day = "20",
doi = "10.1021/acschembio.8b00061",
language = "English",
volume = "13",
pages = "881--886",
journal = "A C S Chemical Biology",
issn = "1554-8929",
publisher = "American Chemical Society",
number = "4",

}

RIS

TY - JOUR

T1 - Inhibition of HIV Fusion by Small Molecule Agonists through Efficacy-Engineering of CXCR4

AU - Berg, Christian

AU - Daugvilaite, Viktorija

AU - Steen, Anne

AU - Jørgensen, Astrid Sissel

AU - Våbenø, Jon

AU - Rosenkilde, Mette Marie

PY - 2018/4/20

Y1 - 2018/4/20

N2 - CXC chemokine receptor 4 (CXCR4) is involved in multiple physiological and pathological processes, notably as a coreceptor for human immunodeficiency virus (HIV) cell entry. Its broad expression pattern and vital biological importance make CXCR4 a troublesome drug target, as disruption of the interaction with its endogenous ligand, CXC chemokine ligand 12 (CXCL12), has severe consequences. In fact, only one CXCR4 drug, the bicyclam antagonist and HIV entry inhibitor AMD3100 (Plerixafor/Mozobil), has been approved for clinical use, however only for stem cell mobilization-a consequence of CXCR4 antagonism. Here, we report the engineering of an efficacy switch mutation in CXCR4-F292A7.43 in the middle of transmembrane helix 7-that converted the antagonists AMD3100 and AMD11070 into partial agonists. As agonists on F292A CXCR4, AMD3100 and AMD11070 were less disruptive to CXCR4 signaling while they remained efficient inhibitors of HIV fusion. This demonstrates that small molecule CXCR4 agonists can have a therapeutic potential as HIV entry inhibitors.

AB - CXC chemokine receptor 4 (CXCR4) is involved in multiple physiological and pathological processes, notably as a coreceptor for human immunodeficiency virus (HIV) cell entry. Its broad expression pattern and vital biological importance make CXCR4 a troublesome drug target, as disruption of the interaction with its endogenous ligand, CXC chemokine ligand 12 (CXCL12), has severe consequences. In fact, only one CXCR4 drug, the bicyclam antagonist and HIV entry inhibitor AMD3100 (Plerixafor/Mozobil), has been approved for clinical use, however only for stem cell mobilization-a consequence of CXCR4 antagonism. Here, we report the engineering of an efficacy switch mutation in CXCR4-F292A7.43 in the middle of transmembrane helix 7-that converted the antagonists AMD3100 and AMD11070 into partial agonists. As agonists on F292A CXCR4, AMD3100 and AMD11070 were less disruptive to CXCR4 signaling while they remained efficient inhibitors of HIV fusion. This demonstrates that small molecule CXCR4 agonists can have a therapeutic potential as HIV entry inhibitors.

U2 - 10.1021/acschembio.8b00061

DO - 10.1021/acschembio.8b00061

M3 - Journal article

C2 - 29461034

VL - 13

SP - 881

EP - 886

JO - A C S Chemical Biology

JF - A C S Chemical Biology

SN - 1554-8929

IS - 4

ER -

ID: 199379437