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

Christian Berg; Viktorija Daugvilaite; Anne Steen; Astrid Sissel Jørgensen; Jon Våbenø; Mette Marie Rosenkilde

doi:10.1021/acschembio.8b00061

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

Christian Berg, Viktorija Daugvilaite, Anne Steen, Astrid Sissel Jørgensen, Jon Våbenø, Mette Marie Rosenkilde

Department of Biomedical Sciences

6 Citations (Scopus)

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.

Original language	English
Journal	ACS chemical biology
Volume	13
Issue number	4
Pages (from-to)	881-886
Number of pages	6
ISSN	1554-8929
DOIs	https://doi.org/10.1021/acschembio.8b00061
Publication status	Published - 20 Apr 2018

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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.",

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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.

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EP - 886

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ER -

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

Abstract

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