PMID- 29461034
OWN - NLM
STAT- MEDLINE
DCOM- 20190405
LR  - 20190405
IS  - 1554-8937 (Electronic)
IS  - 1554-8929 (Linking)
VI  - 13
IP  - 4
DP  - 2018 Apr 20
TI  - Inhibition of HIV Fusion by Small Molecule Agonists through Efficacy-Engineering 
      of CXCR4.
PG  - 881-886
LID - 10.1021/acschembio.8b00061 [doi]
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-F292A(7.43) 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.
FAU - Berg, Christian
AU  - Berg C
AUID- ORCID: 0000-0002-0539-7081
AD  - Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, Faculty 
      of Health and Medical Sciences , University of Copenhagen , Blegdamsvej 3B , 2200 
      Copenhagen N , Denmark.
AD  - Infectious Diseases Unit, Department of Medicine , Herlev-Gentofte Hospital , 
      Herlev Ringvej 75 , 2730 Herlev , Denmark.
FAU - Daugvilaite, Viktorija
AU  - Daugvilaite V
AD  - Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, Faculty 
      of Health and Medical Sciences , University of Copenhagen , Blegdamsvej 3B , 2200 
      Copenhagen N , Denmark.
FAU - Steen, Anne
AU  - Steen A
AD  - Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, Faculty 
      of Health and Medical Sciences , University of Copenhagen , Blegdamsvej 3B , 2200 
      Copenhagen N , Denmark.
FAU - Jorgensen, Astrid Sissel
AU  - Jorgensen AS
AD  - Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, Faculty 
      of Health and Medical Sciences , University of Copenhagen , Blegdamsvej 3B , 2200 
      Copenhagen N , Denmark.
FAU - Vabeno, Jon
AU  - Vabeno J
AD  - Helgeland Hospital Trust , Prestmarkveien 1 , 8800 Sandnessjoen , Norway.
FAU - Rosenkilde, Mette Marie
AU  - Rosenkilde MM
AD  - Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, Faculty 
      of Health and Medical Sciences , University of Copenhagen , Blegdamsvej 3B , 2200 
      Copenhagen N , Denmark.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180227
PL  - United States
TA  - ACS Chem Biol
JT  - ACS chemical biology
JID - 101282906
RN  - 0 (Anti-HIV Agents)
RN  - 0 (CXCR4 protein, human)
RN  - 0 (HIV Fusion Inhibitors)
RN  - 0 (Receptors, CXCR4)
SB  - IM
MH  - Anti-HIV Agents
MH  - HIV Fusion Inhibitors/*chemistry
MH  - HIV-1/*drug effects
MH  - Humans
MH  - Protein Engineering/methods
MH  - Receptors, CXCR4/agonists/antagonists & inhibitors/*drug effects
EDAT- 2018/02/21 06:00
MHDA- 2019/04/06 06:00
CRDT- 2018/02/21 06:00
PHST- 2018/02/21 06:00 [pubmed]
PHST- 2019/04/06 06:00 [medline]
PHST- 2018/02/21 06:00 [entrez]
AID - 10.1021/acschembio.8b00061 [doi]
PST - ppublish
SO  - ACS Chem Biol. 2018 Apr 20;13(4):881-886. doi: 10.1021/acschembio.8b00061. Epub 
      2018 Feb 27.