Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: prevention of reperfusion injury.
The chemokine CXC ligand 8 (CXCL8)/IL-8 and related agonists recruit and activate polymorphonuclear cells by binding the CXC chemokine receptor 1 (CXCR1) and CXCR2. Here we characterize the unique mode of action of a small-molecule inhibitor (Repertaxin) of CXCR1 and CXCR2. Structural and biochemical data are consistent with a noncompetitive allosteric mode of interaction between CXCR1 and Repertaxin, which, by locking CXCR1 in an inactive conformation, prevents signaling. Repertaxin is an effective inhibitor of polymorphonuclear cell recruitment in vivo and protects organs against reperfusion injury. Targeting the Repertaxin interaction site of CXCR1 represents a general strategy to modulate the activity of chemoattractant receptors.
Bertini
Riccardo
R
Dompé, 67100 L'Aquila, Italy.
Allegretti
Marcello
M
Bizzarri
Cinzia
C
Moriconi
Alessio
A
Locati
Massimo
M
Zampella
Giuseppe
G
Cervellera
Maria N
MN
Di Cioccio
Vito
V
Cesta
Maria C
MC
Galliera
Emanuela
E
Martinez
Fernando O
FO
Di Bitondo
Rosa
R
Troiani
Giulia
G
Sabbatini
Vilma
V
D'Anniballe
Gaetano
G
Anacardio
Roberto
R
Cutrin
Juan C
JC
Cavalieri
Barbara
B
Mainiero
Fabrizio
F
Strippoli
Raffaele
R
Villa
Pia
P
Di Girolamo
Maria
M
Martin
Franck
F
Gentile
Marco
M
Santoni
Angela
A
Corda
Daniela
D
Poli
Giuseppe
G
Mantovani
Alberto
A
Ghezzi
Pietro
P
Colotta
Francesco
F
D000494:Allosteric Regulation / Q000502:physiology*; D000818:Animals; D001665:Binding Sites; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008107:Liver Diseases / Q000473:pathology; D008958:Models, Molecular; D011487:Protein Conformation / Q000187:drug effects; D051381:Rats; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors*; D015427:Reperfusion Injury / Q000188:drug therapy / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use
D023062:Receptors, Interleukin-8A; D013449:Sulfonamides; C490707:reparixin