Characterization of a Ten-Cysteine Peptide from Scorpion That Inhibits Classical Complement Activation via C4/C4b
- 1Hubei Key Laboratory of Embryonic Stem Cell Research and Hubei Key Laboratory of Wudang Local Chinese Medicine Research of Institute of Biomedicine, College of Basic Medicine, Hubei University of Medicine, Shiyan 442000, China
- 2Department of Clinical Laboratory, Dongfeng Hospital, Hubei University of Medicine, Shiyan 442008, China
Abstract
Scorpion toxin peptides are useful bioactive substance resources, but no anticomplement peptides have been reported from scorpions. Here, we attempt to explore scorpion-derived anticomplement peptides by scanning a small and specific scorpion toxin peptide library. Given that complement activation constitutes a protease-driven proteolytic cascade reaction, we focused on two kinds of serine protease inhibitor-like peptides from scorpion Kunitz-type and Ascaris-type toxin subfamilies. Assays of complement-mediated erythrocyte lysis showed that one scorpion peptide SjAPI-2, with an Ascaris-type structural fold inhibited classical complement activation in a concentration-dependent manner. Complement-deficient experiments revealed that the anti-complement effect of SjAPI-2 was markedly enhanced in sera reconstituted with deficient complement proteins C3 or C4, and suggested that C3 and C4 are associated with the anticomplement effect of SjAPI-2. Combined ELISA and Co-IP assays further revealed that SjAPI-2 can directly bind to C4 and C4b. These results indicated that SjAPI-2 can inhibit classical complement activation via binding to C4 and C4b, which blocks the upstream proteolytic cleavage of C4 as well as the downstream cleavage and activation of C3. Alanine-scanning mutagenesis showed that SjAPI-2 suppressed complement activation via its functional loop from K30 to V38. Myocardial ischemia–reperfusion injury experiment showed that SjAPI-2 limited the extent of myocardial infarction and exerted a cardioprotective effect in vivo. To the best of our knowledge, SjAPI-2 is the first anticomplement toxin peptide from a scorpion, suggesting that scorpion venom peptides might be a new resource for anticomplement peptide discovery. The unique ten-cysteine peptide scaffold of SjAPI-2 also provided a novel lead drug template for C4/C4b associated complement diseases.
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BibTeX
@article{luo2026characterization,
title = {{Characterization of a Ten-Cysteine Peptide from Scorpion That Inhibits Classical Complement Activation via C4/C4b}},
author = {Xudong Luo and Wen Zhu and Yuwei Wang and Xiaolin Deng and Zhiping Zhai and Wangmei Duan and Xiangdong Ye and Li Ding and Fang Sun and Hongyi Luo and Chenhu Qin and Zongyun Chen},
journal = {Biomolecules},
year = {2026},
month = oct,
doi = {10.3390/biom16101520},
url = {https://www.mdpi.com/2218-273X/16/10/1520},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Characterization of a Ten-Cysteine Peptide from Scorpion That Inhibits Classical Complement Activation via C4/C4b
AU - Xudong Luo
AU - Wen Zhu
AU - Yuwei Wang
AU - Xiaolin Deng
AU - Zhiping Zhai
AU - Wangmei Duan
AU - Xiangdong Ye
AU - Li Ding
AU - Fang Sun
AU - Hongyi Luo
AU - Chenhu Qin
AU - Zongyun Chen
PY - 2026
DA - 2026/10/01
JO - Biomolecules
DO - 10.3390/biom16101520
UR - https://www.mdpi.com/2218-273X/16/10/1520
AB - Scorpion toxin peptides are useful bioactive substance resources, but no anticomplement peptides have been reported from scorpions. Here, we attempt to explore scorpion-derived anticomplement peptides by scanning a small and specific scorpion toxin peptide library. Given that complement activation constitutes a protease-driven proteolytic cascade reaction, we focused on two kinds of serine protease inhibitor-like peptides from scorpion Kunitz-type and Ascaris-type toxin subfamilies. Assays of complement-mediated erythrocyte lysis showed that one scorpion peptide SjAPI-2, with an Ascaris-type structural fold inhibited classical complement activation in a concentration-dependent manner. Complement-deficient experiments revealed that the anti-complement effect of SjAPI-2 was markedly enhanced in sera reconstituted with deficient complement proteins C3 or C4, and suggested that C3 and C4 are associated with the anticomplement effect of SjAPI-2. Combined ELISA and Co-IP assays further revealed that SjAPI-2 can directly bind to C4 and C4b. These results indicated that SjAPI-2 can inhibit classical complement activation via binding to C4 and C4b, which blocks the upstream proteolytic cleavage of C4 as well as the downstream cleavage and activation of C3. Alanine-scanning mutagenesis showed that SjAPI-2 suppressed complement activation via its functional loop from K30 to V38. Myocardial ischemia–reperfusion injury experiment showed that SjAPI-2 limited the extent of myocardial infarction and exerted a cardioprotective effect in vivo. To the best of our knowledge, SjAPI-2 is the first anticomplement toxin peptide from a scorpion, suggesting that scorpion venom peptides might be a new resource for anticomplement peptide discovery. The unique ten-cysteine peptide scaffold of SjAPI-2 also provided a novel lead drug template for C4/C4b associated complement diseases.
SN - 2218-273X
ER -