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

Christina Lamers; Xiaoguang Xue; Martin Smieško; Henri van Son; Bea Wagner; Nadja Berger; Georgia Sfyroera; Piet Gros; John D. Lambris; Daniel Ricklin

doi:10.1038/s41467-022-33003-7

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

Christina Lamers
, Xiaoguang Xue
, Martin Smieško
, Henri van Son
, Bea Wagner
, Nadja Berger
, Georgia Sfyroera
, Piet Gros
, John D. Lambris
, Daniel Ricklin^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	5519
Number of pages	15
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-33003-7
Publication status	Published - 20 Sept 2022

Bibliographical note

Funding Information:
We gratefully thank the European Synchrotron Radiation Facility (ESRF) for the provision of synchrotron radiation facilities and beamline scientists of the ESRF and the European Molecular Biology Laboratory for assistance. This study was supported by grants from the Swiss National Science Foundation (31003A_176104 to D.R.; 205321_204607 to M.S. and D.R.), ZonMW (Top grant 700.54.304 to P.G.), the Netherlands Organization for Scientific Research (01.80.104.00 to P.G.), the European Community′s Seventh Framework Programmes (FP7-IDEAS 233229 to P.G.; FP7-INFRASTRUCTURES 283570 to P.G.) and the U.S. National Institutes of Health (P01AI068730 to J.D.L.), and by the Ralph and Sallie Weaver Professorship in Research Medicine (to J.D.L.). The authors thank Butler SciComm for their excellent language editing service.

Funding Information:
We gratefully thank the European Synchrotron Radiation Facility (ESRF) for the provision of synchrotron radiation facilities and beamline scientists of the ESRF and the European Molecular Biology Laboratory for assistance. This study was supported by grants from the Swiss National Science Foundation (31003A_176104 to D.R.; 205321_204607 to M.S. and D.R.), ZonMW (Top grant 700.54.304 to P.G.), the Netherlands Organization for Scientific Research (01.80.104.00 to P.G.), the European Community′s Seventh Framework Programmes (FP7-IDEAS 233229 to P.G.; FP7-INFRASTRUCTURES 283570 to P.G.) and the U.S. National Institutes of Health (P01AI068730 to J.D.L.), and by the Ralph and Sallie Weaver Professorship in Research Medicine (to J.D.L.). The authors thank Butler SciComm for their excellent language editing service.

Publisher Copyright:
© 2022, The Author(s).

Funding

We gratefully thank the European Synchrotron Radiation Facility (ESRF) for the provision of synchrotron radiation facilities and beamline scientists of the ESRF and the European Molecular Biology Laboratory for assistance. This study was supported by grants from the Swiss National Science Foundation (31003A_176104 to D.R.; 205321_204607 to M.S. and D.R.), ZonMW (Top grant 700.54.304 to P.G.), the Netherlands Organization for Scientific Research (01.80.104.00 to P.G.), the European Community′s Seventh Framework Programmes (FP7-IDEAS 233229 to P.G.; FP7-INFRASTRUCTURES 283570 to P.G.) and the U.S. National Institutes of Health (P01AI068730 to J.D.L.), and by the Ralph and Sallie Weaver Professorship in Research Medicine (to J.D.L.). The authors thank Butler SciComm for their excellent language editing service. We gratefully thank the European Synchrotron Radiation Facility (ESRF) for the provision of synchrotron radiation facilities and beamline scientists of the ESRF and the European Molecular Biology Laboratory for assistance. This study was supported by grants from the Swiss National Science Foundation (31003A_176104 to D.R.; 205321_204607 to M.S. and D.R.), ZonMW (Top grant 700.54.304 to P.G.), the Netherlands Organization for Scientific Research (01.80.104.00 to P.G.), the European Community′s Seventh Framework Programmes (FP7-IDEAS 233229 to P.G.; FP7-INFRASTRUCTURES 283570 to P.G.) and the U.S. National Institutes of Health (P01AI068730 to J.D.L.), and by the Ralph and Sallie Weaver Professorship in Research Medicine (to J.D.L.). The authors thank Butler SciComm for their excellent language editing service.

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@article{f09057032c574e44a078f4d191042338,

title = "Insight into mode-of-action and structural determinants of the compstatin family of clinical complement inhibitors",

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-{\AA} 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.",

author = "Christina Lamers and Xiaoguang Xue and Martin Smie{\v s}ko and \{van Son\}, Henri and Bea Wagner and Nadja Berger and Georgia Sfyroera and Piet Gros and Lambris, \{John D.\} and Daniel Ricklin",

note = "Funding Information: We gratefully thank the European Synchrotron Radiation Facility (ESRF) for the provision of synchrotron radiation facilities and beamline scientists of the ESRF and the European Molecular Biology Laboratory for assistance. This study was supported by grants from the Swiss National Science Foundation (31003A\_176104 to D.R.; 205321\_204607 to M.S. and D.R.), ZonMW (Top grant 700.54.304 to P.G.), the Netherlands Organization for Scientific Research (01.80.104.00 to P.G.), the European Community′s Seventh Framework Programmes (FP7-IDEAS 233229 to P.G.; FP7-INFRASTRUCTURES 283570 to P.G.) and the U.S. National Institutes of Health (P01AI068730 to J.D.L.), and by the Ralph and Sallie Weaver Professorship in Research Medicine (to J.D.L.). The authors thank Butler SciComm for their excellent language editing service. Funding Information: We gratefully thank the European Synchrotron Radiation Facility (ESRF) for the provision of synchrotron radiation facilities and beamline scientists of the ESRF and the European Molecular Biology Laboratory for assistance. This study was supported by grants from the Swiss National Science Foundation (31003A\_176104 to D.R.; 205321\_204607 to M.S. and D.R.), ZonMW (Top grant 700.54.304 to P.G.), the Netherlands Organization for Scientific Research (01.80.104.00 to P.G.), the European Community′s Seventh Framework Programmes (FP7-IDEAS 233229 to P.G.; FP7-INFRASTRUCTURES 283570 to P.G.) and the U.S. National Institutes of Health (P01AI068730 to J.D.L.), and by the Ralph and Sallie Weaver Professorship in Research Medicine (to J.D.L.). The authors thank Butler SciComm for their excellent language editing service. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

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AU - Lamers, Christina

AU - Xue, Xiaoguang

AU - Smieško, Martin

AU - van Son, Henri

AU - Wagner, Bea

AU - Berger, Nadja

AU - Sfyroera, Georgia

AU - Gros, Piet

AU - Lambris, John D.

AU - Ricklin, Daniel

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N2 - 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.

AB - 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.

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

Abstract

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Funding

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