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Design of miniprotein inhibitors targeting complement C9 to block membrane attack complex assembly
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Design of miniprotein inhibitors targeting complement C9 to block membrane attack complex assembly
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Journal Article
Design of miniprotein inhibitors targeting complement C9 to block membrane attack complex assembly
2026
Overview
The abnormal formation of the membrane attack complex (MAC) is intrinsically linked to a range of acute and chronic immune diseases. The insertion of complement C9 into the membrane is the final step and kinetic bottleneck of MAC formation. However, research on blocking the MAC formation of C9 is currently limited. Given its broad, flat, and polar functional interface, complement C9 is a challenging target for rational design. Here, we utilize deep learning-based methods for protein scaffold generation, sequence design, and complex structure prediction to de novo design mini-protein inhibitors that specifically block the membrane insertion of soluble complement C9. The binding affinity of the mini-protein inhibitor is further optimized to 700 pM via partial diffusion. Design accuracy and binding specificity are verified through X-ray crystallography and biochemical studies. An in vivo acute hemolysis inhibition assay reveals that the C9 mini-protein inhibitors remain effective against hemolysis even 8 minutes after complement activation, outperforming the complement C5 inhibitor eculizumab. The de novo designed C9 mini-protein inhibitors can offer an optional therapeutic approach for the prevention and treatment of acute or chronic immune diseases associated with abnormal complement activation.
In this work the authors employed deep learning-based methods to design mini-protein that block membrane insertion of complement C9. These well performed inhibitors provide an alternative approach for preventing diseases associated with abnormal complement activation.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 82/80
/ 82/83
/ Animals
/ Antibodies, Monoclonal, Humanized - pharmacology
/ Binding
/ Blocking
/ Complement Activation - drug effects
/ Complement C9 - antagonists & inhibitors
/ Complement Inactivating Agents - chemistry
/ Complement Inactivating Agents - pharmacology
/ Complement Membrane Attack Complex - antagonists & inhibitors
/ Complement Membrane Attack Complex - chemistry
/ Complement Membrane Attack Complex - metabolism
/ Design
/ E coli
/ Humanities and Social Sciences
/ Humans
/ Proteins
/ Science
/ Success
