4.8 Article

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

Journal

NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41467-022-33003-7

Keywords

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Funding

  1. Swiss National Science Foundation [31003A_176104, 205321_204607]
  2. ZonMW (Top grant) [700.54.304]
  3. Netherlands Organization for Scientific Research [01.80.104.00]
  4. European Communitys Seventh Framework Programmes [FP7-IDEAS 233229, FP7-INFRASTRUCTURES 283570]
  5. U.S. National Institutes of Health [P01AI068730]
  6. Ralph and Sallie Weaver Professorship in Research Medicine
  7. Swiss National Science Foundation (SNF) [205321_204607] Funding Source: Swiss National Science Foundation (SNF)

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The authors provide molecular-level insight into the mode-of-action, target selectivity, and species specificity of the compstatin family of complement inhibitors, which entered the clinic in 2021.
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-angstrom 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. Therapeutic modulation of the complement system has gained interest over the past two decades. Here, the authors provide molecular-level insight into the mode-of-action, target selectivity and species specificity of the compstatin family of complement inhibitors, which entered the clinic in 2021.

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