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Small-molecule factor B inhibitor for the treatment of complement-mediated diseases

2019; National Academy of Sciences; Volume: 116; Issue: 16 Linguagem: Inglês

10.1073/pnas.1820892116

1091-6490

Anna Schubart, Karen Anderson, Nello Mainolfi, Holger Sellner, Takeru Ehara, Christopher M. Adams, Aengus Mac Sweeney, Sha-Mei Liao, Maura Crowley, Amanda Littlewood‐Evans, Sophie Sarret, Grazyna Wieczorek, Ludovic Perrot, Valérie Dubost, Thierry Flandre, Yuzhou Zhang, Richard J. Smith, Antonio M. Risitano, Rajeshri G. Karki, Chun Zhang, Eric Valeur, Finton Sirockin, Bernd Gerhartz, P. Erbel, Nicola Hughes, Thomas M. Smith, Frédéric Cumin, Upendra A. Argikar, Börje Haraldsson, Muneto Mogi, Richard Sedrani, Christian Wiesmann, Bruce Jaffee, Jürgen Maibaum, Stefanie Flohr, R. A. Harrison, Jörg Eder,

Erythrocyte Function and Pathophysiology

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 nephropathy 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.