IJMS, Vol. 26, Pages 10154: Discovery of a Novel Antithrombotic Cystine Knot Peptide from Spider Venom Gland Transcriptome

International Journal of Molecular Sciences doi: 10.3390/ijms262010154

Authors:
Jinai Gao
Di Yang
Wanting Wang
Xiaoshan Huang
Ruiyin Guo
Kaixun Cao
Qiumin Lu
Ziyi Wang
Ren Lai
Juan Li

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.

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Jinai Gao www.mdpi.com