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  3. A novel polypeptide from stony coral Goniopora columna inhibits thrombosis by interfering with the contact-kinin pathway

A novel polypeptide from stony coral Goniopora columna inhibits thrombosis by interfering with the contact-kinin pathway

  • Arch Toxicol. 2025 Jun 4. doi: 10.1007/s00204-025-04090-4.
Qian Chen # 1,  Congshuang Deng # 2,  Xiaoshan Huang # 3,  Kaixun Cao 4,  Hanbin Chen 5,  Yang Chen 3,  Mehwish Khalid 3,  Qiuyue Xu 6,  Qiumin Lu 3 7,  Ziyi Wang 3,  Aili Wang 8,  Ren Lai 9 10
Affiliations

Affiliations

  • 1 Center for Evolution and Conservation Biology, Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, 511458, China.
  • 2 Shenzhen Academy of Environmental Sciences, Shenzhen, 518022, Guangdong, China.
  • 3 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 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, National Resource Center for Non-Human Primates, Kunming Institute of Zoology, The Chinese Academy of Sciences, No.17 Longxin Road, Kunming, 650201, Yunnan, China.
  • 4 College of Life Sciences, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, China.
  • 5 Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China.
  • 6 Department of Clinical Laboratory, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China.
  • 7 Yunnan Characteristic Plant Extraction Laboratory, Yunnan, 650106, China.
  • 8 Center for Evolution and Conservation Biology, Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, 511458, China. allie612@gmlab.ac.cn.
  • 9 Center for Evolution and Conservation Biology, Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, 511458, China. rlai@mail.kiz.ac.cn.
  • 10 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 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, National Resource Center for Non-Human Primates, Kunming Institute of Zoology, The Chinese Academy of Sciences, No.17 Longxin Road, Kunming, 650201, Yunnan, China. rlai@mail.kiz.ac.cn.
  • # Contributed equally.
PMID: 40464975 DOI: 10.1007/s00204-025-04090-4
Abstract

Stony corals (Scleractinia) harbor abundant toxins as part of their survival strategy, and these molecules also provide novel lead candidates for drug development. In this study, we present the first comprehensive investigation of toxin profiles of the understudied Goniopora columna through transcriptome analysis, which has expanded the biochemical diversity of marine organism derived toxins. Then, a novel Kunitz-like polypeptide, named GcKuz1, which exhibits therapeutic potential for thrombosis was selected for functional studies and mechanistic investigation. In vitro experiments revealed that GcKuz1, at 2-16 μM, delayed plasma recalcification time and activated partial thromboplastin time without affecting prothrombin time. In murine models, GcKuz1, at 1-4 mg/kg dosage, significantly inhibited the FeCl3-induced carotid artery thrombosis and the carrageenan-induced mouse tail thrombosis. Moreover, GcKuz1 effectively attenuated thrombo-inflammation and cerebral tissue destruction, as well as restored blood-brain barrier integrity, in the transient middle cerebral artery occlusion model. Through enzyme kinetics assays and surface plasmon resonance (SPR) verification, GcKuz1 was shown to strongly inhibit the enzyme activity of plasma Kallikrein (PKA) and FXIIa, two key factors involved in the contact-kinin pathway, via direct interaction, thereby exerting anticoagulation effects without impairing hemostasis. Notably, safety evaluation highlights the low toxicity, minimal hemolytic activity and reduced bleeding risk of GcKuz1, which underline its clinical availability. In conclusion, as a novel coral-derived protease inhibitor of FXIIa and PK, GcKuz1 offers potential therapeutic benefits in the treatment thrombosis-related cardiovascular diseases treatment by suppressing inflammation and preventing thrombus formation.

Keywords

Anticoagulation; Contact-kinin Pathway; Kunitz peptide; Scleractinia; Serine protease inhibitors.

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