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Insight into mode-of-action and structural determinants of the compstatin family of clinical complement inhibitors

Author

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  • Christina Lamers

    (University of Basel
    Leipzig University)

  • Xiaoguang Xue

    (Utrecht University)

  • Martin Smieško

    (University of Basel)

  • Henri Son

    (Utrecht University)

  • Bea Wagner

    (University of Basel)

  • Nadja Berger

    (University of Pennsylvania)

  • Georgia Sfyroera

    (University of Pennsylvania)

  • Piet Gros

    (Utrecht University)

  • John D. Lambris

    (University of Pennsylvania)

  • Daniel Ricklin

    (University of Basel)

Abstract

With the addition of the compstatin-based complement C3 inhibitor pegcetacoplan, another class of complement targeted therapeutics have recently been approved. Moreover, compstatin derivatives with enhanced pharmacodynamic and pharmacokinetic profiles are in clinical development (e.g., Cp40/AMY-101). Despite this progress, the target binding and inhibitory modes of the compstatin family remain incompletely described. Here, we present the crystal structure of Cp40 complexed with its target C3b at 2.0-Å resolution. Structure-activity-relationship studies rationalize the picomolar affinity and long target residence achieved by lead optimization, and reveal a role for structural water in inhibitor binding. We provide explanations for the narrow species specificity of this drug class and demonstrate distinct target selection modes between clinical compstatin derivatives. Functional studies provide further insight into physiological complement activation and corroborate the mechanism of its compstatin-mediated inhibition. Our study may thereby guide the application of existing and development of next-generation compstatin analogs.

Suggested Citation

  • Christina Lamers & Xiaoguang Xue & Martin Smieško & Henri Son & Bea Wagner & Nadja Berger & Georgia Sfyroera & Piet Gros & John D. Lambris & Daniel Ricklin, 2022. "Insight into mode-of-action and structural determinants of the compstatin family of clinical complement inhibitors," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33003-7
    DOI: 10.1038/s41467-022-33003-7
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    References listed on IDEAS

    as
    1. Bert J. C. Janssen & Agni Christodoulidou & Andrew McCarthy & John D. Lambris & Piet Gros, 2006. "Structure of C3b reveals conformational changes that underlie complement activity," Nature, Nature, vol. 444(7116), pages 213-216, November.
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