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
  • 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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