2. Academic Validation
  3. Small-molecule factor D inhibitors targeting the alternative complement pathway

Small-molecule factor D inhibitors targeting the alternative complement pathway

  • Nat Chem Biol. 2016 Dec;12(12):1105-1110. doi: 10.1038/nchembio.2208.
Jürgen Maibaum 1,  Sha-Mei Liao 2,  Anna Vulpetti 1,  Nils Ostermann 1,  Stefan Randl 3,  Simon Rüdisser 1,  Edwige Lorthiois 1,  Paul Erbel 1,  Bernd Kinzel 1,  Fabrice A Kolb 4,  Samuel Barbieri 1,  Julia Wagner 1,  Corinne Durand 1,  Kamal Fettis 1,  Solene Dussauge 1,  Nicola Hughes 1,  Omar Delgado 2,  Ulrich Hommel 1,  Ty Gould 2,  Aengus Mac Sweeney 5,  Bernd Gerhartz 1,  Frederic Cumin 1,  Stefanie Flohr 1,  Anna Schubart 1,  Bruce Jaffee 2,  Richard Harrison 6,  Antonio Maria Risitano 7,  Jörg Eder 1,  Karen Anderson 2
Affiliations

Affiliations

  • 1 Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, Basel, Switzerland.
  • 2 Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
  • 3 Evonik Japan Co., Shinjuku-ku, Tokyo, Japan.
  • 4 Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
  • 5 Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.
  • 6 Institute of Infection and Immunity, School of Medicine, Cardiff University, Henry Wellcome Building, Heath Park, Cardiff, UK.
  • 7 University of Naples, Department of Clinical Medicine and Surgery, Division of Hematology, Naples, Italy.
PMID: 27775713 DOI: 10.1038/nchembio.2208
Abstract

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.

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