Pharmacological Activities and Mechanisms of Hirudin and Its Derivatives - A Review.

Chen Junren,Zhang Huiqiong,Zhang Yue,Cao Xiaoyu,Li Yanan,Gao Yuqing,Peng Cheng,Peng Fu,Xie Xiaofang,Yin Yanpeng,Li Gangmin

doi:10.3389/fphar.2021.660757

Abstract

Hirudin, an acidic polypeptide secreted by the salivary glands of Hirudo medicinalis (also known as “Shuizhi” in traditional Chinese medicine), is the strongest natural specific inhibitor of thrombin found so far. Hirudin has been demonstrated to possess potent anti-thrombotic effect in previous studies. Recently, increasing researches have focused on the anti-thrombotic activity of the derivatives of hirudin, mainly because these derivatives have stronger antithrombotic activity and lower bleeding risk. Additionally, various bioactivities of hirudin have been reported as well, including wound repair effect, anti-fibrosis effect, effect on diabetic complications, anti-tumor effect, anti-hyperuricemia effect, effect on cerebral hemorrhage, and others. Therefore, by collecting and summarizing publications from the recent two decades, the pharmacological activities, pharmacokinetics, novel preparations and derivatives, as well as toxicity of hirudin were systematically reviewed in this paper. In addition, the clinical application, the underlying mechanisms of pharmacological effects, the dose-effect relationship, and the development potential in new drug research of hirudin were discussed on the purpose of providing new ideas for application of hirudin in treating related diseases.

Highlights

Hirudo medicinalis, belonging to hematophagous leeches, has been used for medical purposes since ancient times
Hirudin could reduce the expression of extracellular matrix (ECM) associated proteins in HK-2 human renal tubule epithelial cells induced by high glucose (HG), which was consistent with the results in previous studies (Zhou et al, 2012). These findings proved that hirudin reduced the expression of ECM markers by inhibiting the HIF-1α/vascular endothelial growth factor (VEGF) signaling pathway in diabetic kidney disease (DKD) renal tubular epithelial cells (Pang et al, 2020a)
Lepirudin has been approved as an anticoagulant for patients with heparin-induced thrombocytopenia (HIT), with the usual dose of 0.4 mg/kg IV bolus followed by 0.15 mg/kg/h IV infusion (Greinacher and Lubenow, 2001)

Summary

INTRODUCTION

Hirudo medicinalis, belonging to hematophagous leeches, has been used for medical purposes since ancient times. Pharmacological Activities of Hirudin than ten diverse hirudin variants (HVs) have been discovered in leech so far These peptides possess high stability and activity, with the minimum dissociation constant of 2.3 × 10–14 mol, and the maximum association constant for binding to thrombin of 4.7 × 108 mol−1 S−1 (Zhang and Lan, 2018). With the development of bioengineering technology, recombinant hirudin (rH) was synthesized by genetic engineering, which possesses similar chemical structure and pharmacological activity to natural hirudin. RH can be produced by bacterial or yeast expression systems, and by a cell-free protein synthesis approach, which can express rH with higher antithrombin activity (Wustenhagen et al, 2020) These methods can increase the expression of recombinant hirudin, the thrombin inhibition constant is still lower than that of natural hirudin, mainly because it lacks the tyrosine residue sulfated at site 63 (Nowak and Schror, 2007).

CONCLUSION AND DISCUSSION

Findings

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