Abstract
The complement pathway is an important part of the immune system, and uncontrolled activation is implicated in many diseases. The human complement component 5 protein (C5) is a validated drug target within the complement pathway, as an anti-C5 antibody (Soliris) is an approved therapy for paroxysmal nocturnal hemoglobinuria. Here, we report the identification, optimization and mechanism of action for the first small-molecule inhibitor of C5 complement protein.
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Data availability
All data generated or analyzed during this study are included in this published article (and its supplementary files). The cryo-EM map is available from the Electron Microscopy Data Bank with accession code EMD-4401. The atomic model has been deposited in the Protein Data Bank with the accession code 6I2X.
Change history
26 July 2019
In the version of this article originally published, numbered compounds were not linked correctly to their respective compound pages. The error has been corrected in the HTML version of this paper.
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Contributions
M. Salcius and D.M. performed the biophysical binding assays to identify and qualify C5 as the target. A. Nguyen produced the recombinant C5 protein variants and the C5–CVF complex. A.D.E. performed complement functional assays on human whole blood, sera of different species and mutant C5 proteins and analyzed the data. L.F. and J.H. performed assays to identify the target of the compound described in the literature and analyzed the data. F.L. screened C5 inhibitors in a serum-based complement assay. K.J., P.B., A. Namil, M.C., V.D., E.M. and N.M. designed C5 inhibitors. K.J., P.B., A. Namil, M.C., V.D. and R.T. synthesized compounds. K.J., M.K., P.B. and J.D. conceived and carried out molecular modeling studies. P.A.H. and M.J.R. performed the X-ray crystallization experiments. M.K. identified potential binding pockets. N.M. and M.M. proposed the idea to identify the target of the complement inhibitor. J.M. and M. Schirle designed and analyzed the C5-protease-sensitivity assays. H.S., C.B. and C.W. determined the cryo-EM structure. K.A., K.J., M.K. and G.A.M. conceived experiments, supervised the work and wrote the manuscript.
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Supplementary Information
Supplementary Tables 1–6, Supplementary Figures 1–5
Supplementary Note 1
Synthetic procedures
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Jendza, K., Kato, M., Salcius, M. et al. A small-molecule inhibitor of C5 complement protein. Nat Chem Biol 15, 666–668 (2019). https://doi.org/10.1038/s41589-019-0303-9
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DOI: https://doi.org/10.1038/s41589-019-0303-9
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