At present, the research and development of marine natural products in the world is in the ascendant, and the member countries of the United States, Japan and Europe are at the forefront in this field. In the United States, the National Research Council and the National Cancer Institute spend more than $50 million annually on the research and development of marine drugs. In recent years, the research funding of marine drugs in the National Institutes of Health has increased to more than 1 1% of the total research funding, which is basically the same as that of synthetic drugs and plant drugs. Japan Institute of Marine Biotechnology and Japan Marine Science and Technology Center spend about $654.38 billion annually on marine drug research and development. The annual funding of the European Marine Science and Technology (MAST) program for the development and research of marine drugs is about $654.38 billion.
The screening of marine natural drugs began in the mid-1960s, and expanded to the screening of antiviral, immunosuppressive, cardiotonic and anti-inflammatory substances after 1970s. In the 1980s, most of them were antibacterial and antifungal. With the research and application of new biotechnology such as genetic engineering, cell engineering and enzyme engineering, the research and development of marine drugs have been further promoted. By 1990s, marine biology has become a mature research discipline, which has laid a good foundation for marine drug research. At present, the main research is anti-cardiovascular and cerebrovascular diseases and anti-AIDS. The results of biological activity screening showed that about 20% of marine extracts or compounds showed different degrees of activity. Among these compounds, there are not only various chemical structure types existing in terrestrial organisms, but also many special chemical structure types. Their specific chemical structure is unmatched by terrestrial natural active substances, which has become the basis of new drug research and development.
China is one of the first countries to use marine life as medicine, and its clinical application history is over 2000 years. Since the founding of New China, the research of marine drugs in China has entered a new era. Since 1978 National Science and Technology Congress put forward the suggestion of "asking for medicine from the ocean" and later put forward the strategic idea of "developing marine lake and marsh resources and building China's blue pharmaceutical industry", the research on marine medicinal resources in China has had a certain foundation. Relevant data show that at present, five kinds of marine drugs in China have been approved for listing by the state: sodium alginate, sugar ester, tetrodotoxin, doxycycline, mannitol nicotinate; In addition, there are 10 kinds of marine health products with healthy brand names.
Second, the research and application of marine drugs
1, antibacterial drugs
Microorganisms symbiotic with marine life are a rich antibacterial treasure house. At present, fatty acids, acrylic acids, phenols, indoles and other compounds with antibacterial activity have been isolated from marine organisms, and a series of marine antibacterial drugs such as cephalosporins have also been developed in China.
2. Antiviral drugs
Terpenes, nucleosides, alkaloids, polysaccharides, heterocyclic compounds and other compounds with antiviral activity have been isolated, and Zhenning injection, acidic extract of pearl oyster and other products have been listed in China.
3. Antitumor drugs
The most promising anti-cancer drugs will come from the ocean, and marine anti-tumor active substances have always been the focus of marine drug research. At present, it has been found that at least 10% of marine biological extracts have anti-tumor activity, including nucleotides, amides, polyethers, macrolides and other compounds, among which cytarabine has formed drugs. Anti-tumor drugs being developed in China include chondroitin 6- sulfate, Haiyangbao capsule, debrominated sea rabbit toxin, sea squirt A(B, C), sea cucumber polysaccharide potassium injection and so on. At present, only 10 marine antineoplastic drugs have entered clinical research, and more are pre-clinical research. "Harmo Zhixue Tablet" made from the ink sac discarded during the processing of cuttlefish in Zhoushan, Zhejiang, has a remarkable effect on various kinds of bleeding such as digestive tract, especially female functional uterine bleeding. Products are exported to Southeast Asian countries, but there is no further research. At present, squid ink has been found to have anti-tumor effect, and there are many studies on its mechanism in China, and great progress has been made, and new discoveries have been made continuously, mainly focusing on immunity.
4. Anti-cardiovascular drugs
Many drugs have been developed to prevent and treat cardiovascular diseases, such as terpenoids, polysaccharides, polyunsaturated fatty acids, peptides, nucleosides, etc., all of which have the effects of inhibiting thrombosis and dilating blood vessels. There are more than 50 kinds of marine biotoxins, which not only have cardiotonic effect, but also have strong antihypertensive effect. At present, there are many studies on the antiarrhythmic effect of tetrodotoxin. In addition, spirulina has a good preventive and adjuvant therapeutic effect on hyperlipidemia and atherosclerosis.
5, digestive system drugs
The effects of starfish saponins and total saponins extracted from marine organisms on gastric ulcer healing are better than those of cimetidine. Chitosan derivatives have definite curative effect and high cure rate on gastric ulcer, and have entered clinical trials. Marine stomach medicine made from domestic pharmaceutical factories and traditional Chinese medicine has achieved good results in clinic.
6, anti-inflammatory and analgesic drugs
Manoalide is the most significant active ingredient isolated from marine natural products, and it is a phosphatase A2 inhibitor. It has been used as a typical anti-inflammatory agent in clinical practice for more than 20 years.
7, urinary system drugs
Fucoidan sulfate has the functions of anticoagulation, reducing blood lipid, preventing thrombosis, resisting tumor, improving microcirculation and inhibiting white blood cells. Clinically, it is used to treat cardiovascular and cerebrovascular diseases, especially to improve renal function and increase creatinine clearance rate of kidney. First of all, it is used to treat chronic renal failure and uremia with obvious curative effect and no toxic or side effects. Now it has entered the clinical research according to the national second-class new drug approval.
8. Development and utilization of marine non-edible resources
The development direction of marine drugs mainly focuses on non-edible resources, with rich varieties and resources. According to the investigation, there are more than 654.38+ten thousand species of mollusks, ten thousand species of coelenterates1.1.million species of sponges1.million species, six thousand species of echinoderms and two thousand species of spherical animals. The development and utilization of marine non-edible resources is of great significance. Not only can special drugs be obtained from it, but the remaining protein and polysaccharide after extracting its active components can be used as food and additives, and some of them can be used as feed for secondary development, so as to improve the utilization rate of resources and avoid competition with edible resources.
9, the development and utilization of Chinese patent medicine and Chinese herbal medicine.
Due to the overfishing of marine living resources, natural resources can not meet the growing demand. It is necessary to develop traditional mariculture in a planned way, expand the variety of mariculture, increase the source of medicine, and make a series of marine Chinese patent medicines to promote sales and promote the development of mariculture. Therefore, the development and research should pay attention to the combination of the advantages of marine drug resources and traditional Chinese medicine resources, excavate and sort out the remedies, prescriptions and secret recipes with definite curative effects, match with the marine drug sources, strengthen scientific prescription, and make new dosage forms with convenient use. For example, the output value of soft capsules made of ancient Huoxiang Zhengqi water combined with marine medicine sources is over 100 million, which is a good example. In recent years, reports on the treatment of tumors and cardiovascular diseases with Chinese herbal medicines have multiplied. Among them, the common Chinese herbal medicines are seaweed, kelp, oyster, concha Haliotidis, cuttlefish bone, concha arcae, laver, sea cucumber, scallop, syngnathus, hippocampus, mother-of-pearl, shark liver oil, shark cartilage and so on, which should be carefully planned and rationally developed.
10, functional food
Through deep processing of active ingredients in marine organisms, marine functional food with unique flavor and remarkable health care function is made, which broadens the research field of marine drugs and has great practical significance. These active substances include chitin and its derivatives, fish oil health products, seaweed health products, concentrated hydrolyzed protein, taurine, vitamins, phospholipids, active polysaccharides, dietary fiber, mineral elements and so on.
Three. Key areas of marine drug research
(1) Study on marine anticancer drugs. The research of marine anticancer drugs has always been the dominant one. Scientists predict that the most promising anticancer drugs will come from the ocean. It has been found that at least 10% of marine biological extracts have anti-tumor activity. Every year, 65,438+0,500 marine products are isolated in the United States, and 65,438+0% of them have anticancer activity. At present, at least 10 marine anticancer drugs have entered the clinical or preclinical research stage. Expanding the activity screening of marine organisms, continuing to search for high-efficiency anticancer compounds, directly using them in clinic or as precursors of structural transformation, and developing new high-efficiency and low-toxicity anticancer components will become the development trend of marine anticancer drug research.
(2) Research on marine cardiovascular and cerebrovascular drugs. At present, many drugs have been developed to effectively prevent and treat cardiovascular and cerebrovascular diseases. For example, highly unsaturated fatty acids can inhibit thrombosis and dilate blood vessels, and now many preparations have been used in clinic. More than 50 kinds of marine biotoxins not only have cardiotonic effect, but also have strong antihypertensive effect. At present, there are many studies on the antiarrhythmic effect of tetrodotoxin. In addition, there are sodium alginate and spirulina, which have good preventive and adjuvant therapeutic effects on hyperlipidemia and atherosclerosis.
(3) Research on marine antibacterial and antiviral drugs. Microorganisms living in marine animals and plants are rich in antibacterial resources. Japanese scholars have found that about 27% of marine microorganisms have antibacterial activity.
(4) Research on drugs of marine digestive system. For example, starfish saponin separated from starfish and total saponin extracted from starfish can treat gastric ulcer. The latter has stronger healing effect on gastric ulcer than carboxymethyl derivatives of cimetidine and chitosan, and its trade name is "Weikean" capsule, which has definite curative effect and high cure rate and has entered clinical research. Dalian Chinese Medicine Factory cooperated with Chinese medicine to make "Ocean Stomach Medicine", which achieved good results in clinical application.
(5) Research on marine anti-inflammatory and analgesic drugs. Manoalide is the most significant active ingredient isolated from marine natural products, and it is a phosphatase A2 inhibitor, which has been used as a typical anti-inflammatory agent in clinical trials in the mid-1980s.
(6), marine urinary system drug research. Fucoidan sulfate is a kind of water-soluble polysaccharide, which has the functions of anticoagulation, blood lipid reduction, antithrombosis, microcirculation improvement, detoxification, leukocyte inhibition and anti-tumor. Clinically, it is used to treat cardiovascular and cerebrovascular diseases, especially to improve renal function and increase the creatinine clearance rate of renal spoils. For the first time at home and abroad, it is used to treat chronic renal failure and save uremia patients, with remarkable curative effect and no toxic and side effects. At present, it has entered the clinical research according to the second-class new drug approved by the state, and the trade name is "Shenhaikang".
(7) Research on marine immunomodulatory drugs. Marine natural products are important sources of immunomodulators. Keratin is a kind of sulfated polysaccharide from macroalgae, which has immunomodulatory activity and is widely used as immunosuppressant and cell response regulator in kidney transplantation.
(8) Research on other marine drugs. Other researches such as nervous system drugs and antiallergic drugs have also made great achievements. The ocean is a place for the survival and reproduction of new species of microorganisms. A series of highly effective antibacterial drugs can be cultivated from many new microbial species. For example, Teleocidin from various Streptomyces is a strong antibacterial drug. Marine toxins are the fastest growing field in marine biological research, and most of them have unique chemical structures. Because many highly toxic toxins are based on their highly specific effects on biological nervous system or cardiovascular system, these toxins and their mechanisms of action are important guiding compounds and clues for discovering new drugs for nervous system or cardiovascular system, and can also be used as the basis for finding new pesticides. The chemical structures of marine toxins found at present can be roughly divided into polyether compounds, nitrogen-containing compounds, hypoglycemic lipids, amnesiac amino acid shellfish poisoning, ester-soluble phenols and phosphorus-containing complexes.
(9) Research and development of marine functional food. How to use the active ingredients in marine organisms for deep processing to make marine functional food with unique flavor and remarkable health care effect is an important research field at present.
These include taurine, fish oil unsaturated fatty acids and phospholipids, chitin and chitosan, active polysaccharides, vitamins, dietary fiber, mineral elements and so on. The development trend of marine functional food is to research and develop new varieties of marine functional food with high technology content, high function and high benefit by using multidisciplinary modern high-tech means, and to preserve the natural characteristics and nutritional components of marine life as much as possible.
Four. General situation of marine drug research abroad
The particularity of marine ecological environment leads to the biodiversity of marine drugs, which often contain strange and novel chemicals with pharmacological specificity, high activity and diversity. Up to now, there are 22 classes 1822 genera, 30 18 species of marine life found in shallow sea, offshore and near islands and reefs.
The main biological types of marine drug research are: (1) seaweeds, such as kelp, seaweed, spirulina, Sargassum fusiforme, Sargassum thunbergii, etc. (2) Molluscs, such as oysters, pearls, octopus, concha Haliotidis, clams, etc. ; (3) Arthropods such as lobsters, prawns and hermit crabs; (4) echinoderms, such as sea cucumbers, sea urchins, starfish and petrels; (5) Chordata animals, such as seahorses, sea dragons, sea eels, hairtail, etc. (6) coelenterates, such as corals, jellyfish and pumice; (7) Microorganisms, such as sponges, sea squirts, bryozoa, microalgae, bacteria and fungi. Tropical and temperate marine life is the focus of research, among which marine invertebrates are the most fully studied.
With the continuous expansion of the research scope, the marine life involved has gradually expanded to resources and extreme environmental resources that are difficult to obtain by conventional equipment and conditions such as the far sea, deep sea, polar regions, high temperature, cold and high pressure. At present, more than 20,000 kinds of marine natural products have been isolated from various marine organisms, and the newly discovered compounds are increasing at an average rate of 50% every four years. The structure of marine natural products covers most major structural types, including sugars, polysaccharides, amino acids, protein, inorganic salts, saponins, sterols, alkaloids, terpenoids, macrolides and nucleosides. Screening targets are mainly used to treat cancer, cardiovascular and cerebrovascular diseases, viral infections (AIDS, etc. ) and other difficult diseases that seriously endanger human health.
In recent years, a large number of patents on marine natural products involving medicines, foods, functional foods, cosmetics, enzyme preparations and biological tools have appeared abroad. The pharmacological activities of marine active substances mainly include central nervous system function, anti-tumor function, antibacterial and antiviral function, cardiovascular and cerebrovascular system function, anti-inflammatory, analgesic, antioxidant, hypoglycemic and so on. Many compounds have the potential to develop new drugs. The classic marine drugs that have been put into use in the world include cephalosporin, cytarabine, cytarabine and so on. These are also the earliest modern marine drugs successfully developed and have been widely used in clinic. The typical drug successfully developed in recent years is Ziconotide, which is an analgesic drug from the Indian Pacific snail. Its precursor compound is snail peptide toxin ω-contoxin, which can be obtained by synthesis. The drug obtained the FDA certificate in June 2000, showing a broad application prospect. At present, there are about 20 kinds of marine natural products or their structural analogues in the world, most of which are anticancer drugs. More compounds are in preclinical research stage.