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

Christina Lamers, Xiaoguang Xue, Martin Smieško, Henri Son, Bea Wagner, Nadja Berger, Georgia Sfyroera, Piet Gros, John D. Lambris () and Daniel Ricklin ()
Additional contact information
Christina Lamers: University of Basel
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

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-33003-7 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33003-7

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-33003-7

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().