Derivatives of erythropoietin that are tissue protective but not erythropoietic.
Erythropoietin (EPO) is both hematopoietic and tissue protective, putatively through interaction with different receptors. We generated receptor subtype-selective ligands allowing the separation of EPO's bioactivities at the cellular level and in animals. Carbamylated EPO (CEPO) or certain EPO mutants did not bind to the classical EPO receptor (EPOR) and did not show any hematopoietic activity in human cell signaling assays or upon chronic dosing in different animal species. Nevertheless, CEPO and various nonhematopoietic mutants were cytoprotective in vitro and conferred neuroprotection against stroke, spinal cord compression, diabetic neuropathy, and experimental autoimmune encephalomyelitis at a potency and efficacy comparable to EPO.
Leist
Marcel
M
H. Lundbeck A/S, 2500 Valby, Denmark.
Ghezzi
Pietro
P
Grasso
Giovanni
G
Bianchi
Roberto
R
Villa
Pia
P
Fratelli
Maddalena
M
Savino
Costanza
C
Bianchi
Marina
M
Nielsen
Jacob
J
Gerwien
Jens
J
Kallunki
Pekka
P
Larsen
Anna Kirstine
AK
Helboe
Lone
L
Christensen
Søren
S
Pedersen
Lars O
LO
Nielsen
Mette
M
Torup
Lars
L
Sager
Thomas
T
Sfacteria
Alessandra
A
Erbayraktar
Serhat
S
Erbayraktar
Zubeyde
Z
Gokmen
Necati
N
Yilmaz
Osman
O
Cerami-Hand
Carla
C
Xie
Qiao-Wen
QW
Coleman
Thomas
T
Cerami
Anthony
A
Brines
Michael
M
D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D002478:Cells, Cultured; D003929:Diabetic Neuropathies / Q000188:drug therapy; D015195:Drug Design; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy; D004920:Erythropoiesis; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006400:Hematocrit; D006801:Humans; D008024:Ligands; D051379:Mice; D008809:Mice, Inbred C3H; D016296:Mutagenesis; D009422:Nervous System Diseases / Q000188:drug therapy*; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017467:Receptors, Erythropoietin / Q000378:metabolism; D011994:Recombinant Proteins; D015398:Signal Transduction; D013117:Spinal Cord Compression / Q000188:drug therapy; D020521:Stroke / Q000188:drug therapy; D013329:Structure-Activity Relationship
D008024:Ligands; D018696:Neuroprotective Agents; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; C488171:carbamylated erythropoietin; D004921:Erythropoietin