2. Academic Validation
  3. Discovery of a Novel Anticoagulant Cystine Knot Peptide from Spider Venom Gland Transcriptome

Discovery of a Novel Anticoagulant Cystine Knot Peptide from Spider Venom Gland Transcriptome

  • Int J Mol Sci. 2025 Oct 19;26(20):10154. doi: 10.3390/ijms262010154.
Jinai Gao 1 2 3 4,  Di Yang 5,  Wanting Wang 1 4,  Xiaoshan Huang 1 4,  Ruiyin Guo 6,  Kaixun Cao 1 4,  Qiumin Lu 1 4,  Ziyi Wang 1 4,  Ren Lai 1 4,  Juan Li 1 4
Affiliations

Affiliations

  • 1 Engineering Laboratory of Peptides of Chinese Academy of Sciences, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), State Key Laboratory of Genetic Evolution & Animal Models, Sino-African Joint Research Center, and New Cornerstone Science Laboratory, Kunming Institute of Zoology, Chinese Academy of Sciences, No. 17 Longxin Road, Kunming 650201, China.
  • 2 School of Molecular Medicine, Hangzhou Institute for Advanced Study, Hangzhou 310024, China.
  • 3 Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
  • 4 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5 College of Biological Sciences, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA.
  • 6 Center for Evolution and Conservation Biology, Southern Marine Science and Engineering Guangdong Laboratory, Guangzhou 511458, China.
PMID: 41155448 DOI: 10.3390/ijms262010154
Abstract

The development of effective anticoagulants remains a critical need in modern medicine, particularly for preventing and treating thromboembolic disorders, such as arterial thrombosis and deep vein thrombosis (DVT), as well as complications like ischemic stroke. This study identifies a cysteine-knotted peptide GC38 (sequence: GCSGKGARCAPSKCCSGLSCGRHGGNMYKSCEWNWKTG) derived from the venom gland transcriptome of the Macrothele sp. spider, which exerts thrombus-inhibitory effects by potentiating activated protein C (APC) activity. In vitro assays reveal that GC38 enhances APC activity, prolongs plasma clotting time, and shows no significant cytotoxicity or hemolytic activity. Mechanistically, GC38 interacts allosterically with APC; biolayer interferometry (BLI) confirms this direct interaction, with a dissociation constant KD of 6.16 μM. Additionally, three in vivo thrombosis models (FeCl3-induced arterial occlusion, stasis-induced DVT, and cortical photothrombotic stroke) consistently demonstrated that GC38 was effective in alleviating thrombus formation, with tail-bleeding assays confirming its low hemorrhagic risk. Collectively, our findings position GC38 as a pioneering spider venom-derived lead molecule that addresses dual arterial and venous antithrombotic actions. This opens new avenues for developing spider venom-derived peptides as therapeutic agents targeting intravascular coagulation in arteries and veins.

Keywords

activated protein C; anticoagulant therapy; cysteine-knot peptide; thrombosis models; venom peptide diversity.

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