Chronic dysregulation of alternative complement pathway activation has been associated with diverse clinical disorders including age-related macular degeneration resulting in a slow progressing loss of central vision and paroxysmal nocturnal hemoglobinurea characterized by destruction of red blood cells. Factor D is a S1 serine protease with a narrow specificity for arginine in the P1 position, which catalyses the first enzymatic reaction of the amplification loop of the alternative complement pathway. In the quest for inhibitors of Factor D no validated hits were identified from two HTS campaigns. This prompted us to conduct two alternative hit finding approaches: a) <i>in silico</i> active site mapping for hot spots identification to guide rational structure-based design of a focussed library and b) NMR screening of focussed and diverse fragment libraries. The wealth of information gathered by these complementary approaches enabled the identification of ligands binding to different sub-pockets and conformations of Factor D and was instrumental for the generation of the first known in vivo potent non-covalent orally bioavailable reversible Factor D inhibitors with excellent potency in 50% human whole blood in vitro and sustained oral and ocular efficacy in a model of lipopolysaccharide (LPS)-induced systemic AP activation in mice expressing human Factor D.

Structure-based design of small-molecule Factor D inhibitors targeting the alternative complement pathway

255th National Meeting (2018)

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