Views: 0 Author: Site Editor Publish Time: 2023-01-04 Origin: Site
Hirudin, a small molecule polypeptide composed of 65-66 amino acids, is one of the most active and well studied components extracted from leeches and their salivary glands. Hirudo is rich in hirudin, which has a strong inhibitory effect on thrombin and is the strongest natural specific inhibitor of thrombin found so far. Hirudin has strong anticoagulant and antithrombotic effects, and has broad application prospects in clinical treatment and prevention of various thrombosis.
Leeches belong to highly specialized annelids. They were first recorded in the Shennong's Herbal Classic, commonly known as leeches. They are traditional Chinese medicine, salty, bitter, and neutral in nature. According to the Pharmacopoeia of the People's Republic of China, it has the effect of breaking blood, removing blood stasis and unblocking menstruation. It is mainly used to treat tumor, mass, blood stasis, amenorrhea and traumatic injuries. In 1884, Haycraft first found a bioactive substance hirudin in the salivary glands of European medical leeches. In 1927, Shionoya first studied it as an effective antithrombotic drug.
1955 Markwardt pointed out that it was a protein substance and named it hirudin. Natural hirudin is an anticoagulant protein extracted from medical leeches. It is a single chain polypeptide composed of 65 or 66 amino acid residues, with a relative molecular weight of 7000 Dalton. There are three pairs of disulfide bonds at the N-terminal of hirudin, which make the N-terminal peptide chain fold into a dense cyclic peptide structure and stabilize the protein structure. Its N terminal contains an active center, which can recognize and bind to the substrate, namely, the basic amino acid enrichment site of thrombin. The C-terminal is rich in acidic amino acid residues, and 6 of the last 9 amino acids are acidic amino acids.
There is a special sequence composed of Pro Lys Pro in the middle of hirudin peptide chain, which is not degraded by general protease. This structure has two functions: ① maintain the stability of hirudin molecule; ② Guide hirudin molecules to combine with thrombin molecules in the right direction.
Animal tests and clinical studies have shown that hirudin can effectively prevent blood clotting and thrombosis, as well as prevent thrombin catalyzed activation of coagulation factors and platelet reaction and other further blood stasis phenomena. In addition, it can inhibit the proliferation of fibroblasts induced by thrombin and the stimulation of thrombin on endothelial cells. Compared with heparin, it is not only less used, does not cause bleeding, and does not depend on endogenous cofactors; Heparin, on the other hand, may cause bleeding. Antithrombin III is often reduced during the pathogenesis of disseminated intravascular coagulation, which will limit the efficacy of heparin. Hirudo will have a better effect.
Hirudin is a kind of promising anticoagulant and blood stasis removing drug. It can be used to treat various thrombotic diseases, especially venous thrombosis and diffuse vascular coagulation; It can also be used to prevent the formation of arterial thrombosis after surgery, and prevent the formation of thrombosis after thrombolysis or vascular reconstruction; Improve extracorporeal blood circulation and hemodialysis process. In microsurgery, vascular embolism at the anastomosis often leads to failure. Hirudin can promote wound healing. Research also shows that hirudin can also play a role in tumor treatment. It can prevent the metastasis of tumor cells, and has been proved to be effective for tumors such as fibrosarcoma, osteosarcoma, angiosarcoma, melanoma and leukemia. Hirudin can also be used in combination with chemotherapy and radiotherapy to enhance the therapeutic effect by promoting blood flow in tumors.
Animal tests and clinical studies have shown that intravenous or subcutaneous injection of hirudin has no obvious toxic and side effects. No matter in acute or subacute toxicity tests, it has no effect on blood pressure, heart rate, blood phase, bleeding time and blood chemical composition, and has no effect on the respiratory system, no allergic reaction, and generally no specific antibody is found. LD50>50mgAg, which is much higher than the dose used for treatment (1mgAg). It is particularly worth pointing out that hirudin can be taken orally, which brings great convenience to medication. Hirudin is relatively stable, trypsin and chymotrypsin do not destroy its activity, and some hydrolytic fragments of hirudin still have the effect of inhibiting thrombin, which can explain why oral leech extract is still effective.
New drugs containing leeches are also being studied and introduced. Further clinical research is needed to produce recombinant hirudo polypeptide drugs by genetic engineering to replace hirudin or as an additive component of anticoagulant and stasis removing drugs. The development of recombinant hirudin peptide drugs will bring huge social and economic benefits.
1. Hirudin and hirudin do not need antithrombin III (AT - III) as a cofactor to inhibit thrombin reaction, which makes its anticoagulation effect more consistent with the dose effect relationship, and can be used in patients lacking antithrombin III (such as diffuse intravascular coagulation).
2. Heparin cannot inactivate thrombin on nodules and thrombus. Hirudin and hirudin can inhibit thrombin in circulation and thrombus.
3. Heparin will be bound by platelet factor 4 (PTF4) released by activated platelets or glycoproteins rich in amino acids, while hirudin and hirudin are not affected by these factors.
4. Hirudin and hirudin peptide are used for antithrombotic therapy, with less side effects of bleeding, and no allergic reaction and no toxic reaction of immunogenicity.
Cardiovascular system diseases and tumors are two major categories of diseases that mainly endanger human health. Drugs to prevent and treat these two categories of diseases are the focus of new drug development. The efficacy of hirudo in breaking blood, removing blood stasis, dredging meridians and eliminating symptoms has been proved by thousands of years of Chinese medicine practice in China, and the role of recombinant hirudin in anticoagulation and thrombolysis, as well as in combination with tumor chemotherapy and radiotherapy has also been proved by foreign clinical practice. The requirements for injection are high. It is estimated that at least hundreds of millions of yuan of economic benefits can be obtained by replacing leeches with recombinant hirudin polypeptide drugs or as an additive component of Chinese patent medicines. With the expansion of clinical trials, it will be able to be used for the prevention and treatment of more diseases, with a very broad development prospect.