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.
Dompé, 67100 L'Aquila, Italy.
Riccardo
R
Bertini
Marcello
M
Allegretti
Cinzia
C
Bizzarri
Alessio
A
Moriconi
Massimo
M
Locati
Giuseppe
G
Zampella
Maria N
MN
Cervellera
Vito
V
Di Cioccio
Maria C
MC
Cesta
Emanuela
E
Galliera
Fernando O
FO
Martinez
Rosa
R
Di Bitondo
Giulia
G
Troiani
Vilma
V
Sabbatini
Gaetano
G
D'Anniballe
Roberto
R
Anacardio
Juan C
JC
Cutrin
Barbara
B
Cavalieri
Fabrizio
F
Mainiero
Raffaele
R
Strippoli
Pia
P
Villa
Maria
M
Di Girolamo
Franck
F
Martin
Marco
M
Gentile
Angela
A
Santoni
Daniela
D
Corda
Giuseppe
G
Poli
Alberto
A
Mantovani
Pietro
P
Ghezzi
Francesco
F
Colotta
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