Small-molecule factor D inhibitors targeting the alternative complement pathway
| Autor: | Frederic Cumin, Bernd Kinzel, Anna Vulpetti, Antonio M. Risitano, Richard A. Harrison, Kamal Fettis, Aengus Mac Sweeney, Stefan Andreas Randl, Edwige Lorthiois, Fabrice A. Kolb, Nils Ostermann, Solene Dussauge, Corinne Durand, Nicola Hughes, Bernd Gerhartz, Karen Anderson, Samuel Barbieri, Paul Erbel, Omar Delgado, Jörg Eder, Ulrich Hommel, Stefanie Flohr, Simon Rüdisser, Anna Schubart, Ty Gould, Bruce D Jaffee, Jürgen Maibaum, Julia Wagner, Sha-Mei Liao |
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| Přispěvatelé: | Maibaum, Jürgen, Liao, Sha Mei, Vulpetti, Anna, Ostermann, Nil, Randl, Stefan, Rüdisser, Simon, Lorthiois, Edwige, Erbel, Paul, Kinzel, Bernd, Kolb, Fabrice A, Barbieri, Samuel, Wagner, Julia, Durand, Corinne, Fettis, Kamal, Dussauge, Solene, Hughes, Nicola, Delgado, Omar, Hommel, Ulrich, Gould, Ty, Sweeney, Aengus Mac, Gerhartz, Bernd, Cumin, Frederic, Flohr, Stefanie, Schubart, Anna, Jaffee, Bruce, Harrison, Richard, Risitano, ANTONIO MARIA, Eder, Jörg, Anderson, Karen |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Lipopolysaccharides Models Molecular medicine.medical_treatment Complement Pathway Alternative Biology Small Molecule Libraries 03 medical and health sciences Mice Structure-Activity Relationship 0302 clinical medicine medicine Animals Humans Enzyme Inhibitors Molecular Biology Protease Innate immune system Complement component 3 Dose-Response Relationship Drug Molecular Structure Cell Biology medicine.disease Small molecule Complement system Cell biology Mice Inbred C57BL 030104 developmental biology 030220 oncology & carcinogenesis Alternative complement pathway Paroxysmal nocturnal hemoglobinuria biology.protein Factor D Complement Factor D |
| Zdroj: | Nature chemical biology. 12(12) |
| ISSN: | 1552-4469 |
| Popis: | Complement is a key component of the innate immune system, recognizing pathogens and promoting their elimination. Complement component 3 (C3) is the central component of the system. Activation of C3 can be initiated by three distinct routes-the classical, the lectin and the alternative pathways-with the alternative pathway also acting as an amplification loop for the other two pathways. The protease factor D (FD) is essential for this amplification process, which, when dysregulated, predisposes individuals to diverse disorders including age-related macular degeneration and paroxysmal nocturnal hemoglobinuria (PNH). Here we describe the identification of potent and selective small-molecule inhibitors of FD. These inhibitors efficiently block alternative pathway (AP) activation and prevent both C3 deposition onto, and lysis of, PNH erythrocytes. Their oral administration inhibited lipopolysaccharide-induced AP activation in FD-humanized mice. These data demonstrate the feasibility of inhibiting the AP with small-molecule antagonists and support the development of FD inhibitors for the treatment of complement-mediated diseases. |
| Databáze: | OpenAIRE |
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