학술논문
Small-molecule factor B inhibitor for the treatment of complement-mediated diseases
Document Type
Report
Author
Schubart, Anna; Anderson, Karen; Mainolfi, Nello; Sellner, Holger; Ehara, Takeru; Adams, Christopher M.; Sweeney, Aengus Mac; Liao, Sha-Mei; Crowley, Maura; Littlewood-Evans, Amanda; Sarret, Sophie; Wieczorek, Grazyna; Perrot, Ludovic; Dubost, Valerie; Flandre, Thierry; Zhang, Yuzhou; Smith, Richard J.H.; Risitano, Antonio M.; Karki, Rajeshri G.; Zhang, Chun; Valeur, Eric; Sirockin, Finton; Gerhartz, Bernd; Erbel, Paulus; Hughes, Nicola; Smith, Thomas M.; Cumin, Frederic; Argikar, Upendra A.; Haraldsson, Borje; Mogi, Muneto; Sedrani, Richard; Wiesmann, Christian; Jaffee, Bruce; Maibaum, Jurgen; Flohr, Stefanie; Harrison, Richard; Eder, Jorg
Source
Proceedings of the National Academy of Sciences of the United States. April 16, 2019, Vol. 116 Issue 16, p7926, 6 p.
Subject
Language
English
ISSN
0027-8424
Abstract
Dysregulation of the alternative complement pathway (AP) predisposes individuals to a number of diseases including paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and C3 glomerulopathy. Moreover, glomerular Ig deposits can lead to complement-driven nephropathies. Here we describe the discovery of a highly potent, reversible, and selective small-molecule inhibitor of factor B, a serine protease that drives the central amplification loop of the AP. Oral administration of the inhibitor prevents KRN-induced arthritis in mice and is effective upon prophylactic and therapeutic dosing in an experimental model of membranous ne-phropathy in rats. In addition, inhibition of factor B prevents complement activation in sera from C3 glomerulopathy patients and the hemolysis of human PNH erythrocytes. These data demonstrate the potential therapeutic value of using a factor B inhibitor for systemic treatment of complement-mediated diseases and provide a basis for its clinical development. complement | alternative pathway | factor B | drug discovery | nephropathy