Natural active oligopeptides have good drug likeness and play an important role in the body's life activities. They can be directly absorbed by the human intestine and are easier to enter the blood than amino acids. They have attracted extensive attention from chemists and biologists at home and abroad, such as tyrosyl leupeptin with anti-tumor activity[1]Glutathione with hepatoprotective activity[2], thymopentin with enhanced immune activity[3]Et al. However, there are some bottlenecks in the discovery and design of oligopeptide drugs, such as the immature design theory of oligopeptide drugs and the way of discoveryThe discovery of natural active oligopeptides is very limited, which leads to the slow progress of such drugs in recent years[4-6]At present, the search for small molecule active oligopeptides as drugs or lead compounds has become one of the research hotspots in the pharmaceutical field at home and abroad[7]。
As a high-quality natural oligopeptide library, traditional Chinese medicine is characterized by its structural diversity and long-term clinical application. Modern research shows that Chinese medicine oligopeptides have important biological activities such as neuroprotection, liver protection, antitumor, anticoagulant, antioxidant, and enhancing immunity. For example, ginseng affects neuroactive Oligopeptides[8-9]（ACE）Tripeptide[10], liver protective oligopeptide from turtle shell[11-13], Tianlong antitumor Oligopeptides[14], oligopeptides from pilose antler that promote osteoblast proliferation[15], earthworm antitumor oligopeptide[16], leech anticoagulant oligopeptide[17]And antioxidant oligopeptides from mother of Pearl[18]Et al.
This paper is mainly based on the recent10This paper reviews the research progress of oligopeptides in traditional Chinese medicine in recent years, classifies them according to the clinical efficacy of traditional Chinese medicine from which natural oligopeptides are derived, summarizes the sequence and biological activity of various kinds of oligopeptides, and explores the association between active oligopeptides and the classification of traditional Chinese medicine, in order to dig deeply into traditional Chinese medicine as a treasure house of natural active oligopeptides.
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1 near10Research overview of oligopeptides of traditional Chinese medicine in
According to the literature review, the recent10In recent years, the research on oligopeptides of traditional Chinese medicine has mainly focused on19According to the clinical efficacy of traditional Chinese medicine, they are divided into10. The oligopeptide sequences and related activities reported in the study are shown in table1。
2 biological activity
2.1 anticoagulant activity
In recent years, the incidence and mortality of cardio cerebrovascular and thrombotic diseases remain high, which poses a serious threat to the health of middle-aged and elderly people. At present, anticoagulation therapy is the main measure to deal with thromboembolic diseases[53]Rhizoma sparganii is widely used in cardiovascular and cerebrovascular diseases, Liu Bei et al[20]Obtained from the alcohol extract of Sparganium3Cyclic dipeptides, respectivelycyclo-(Tyr-Leu)、cyclo-(Phe-Phe)、cyclo-(Phe-Tyr), will3The anticoagulant activity of seed cyclic dipeptide was measured, and the results showed that the plasma prothrombin time of rats was significantly prolonged in vitro（PT）Activated partial thromboplastin time（APTT）, thrombin time（TT）, exhibiting anticoagulant activity tocyclo-(Phe-Tyr) Its anticoagulant effect is particularly significant and presents a certain dose effect relationship. Leeches are commonly used in clinicTraditional Chinese medicine for activating blood circulation and removing blood stasis, Wanming[43]A large number of studies have been done on the anticoagulant oligopeptides of leech (leech), and the relative molecular mass obtained by extraction and separation is1 880.6And the relative molecular mass was determined to be1 880.6The peptide is one of the material bases for the anticoagulant activity of leech leech, which can significantly prolong the plasmaPT、APTTIts mechanism of action is to interfere with the activity of internal and external coagulation factors, thereby inhibiting the conversion of prothrombin to thrombin and inhibiting the conversion process of fibrinogen to fibrin.
2.2 Hypoxia resistance activity
When the body is hypoxic, it will not only affect many physiological functions in the body, such as endocrine, nervous, respiratory, digestive and other systems, but also make the metabolism of a variety of energy substances in the body disordered, leading to disease and affecting people's health[54-56]Therefore, it is of great significance to find effective anti hypoxia drugsBALB/CMice were subjected to normobaric hypoxia tolerance test, sodium nitrite poisoning survival test, and acute cerebral ischemic hypoxia test to explore ginseng Oligopeptides（GOP）The results showed thatGOPIt can prolong the survival time of normal pressure hypoxia tolerance in mice, and the survival time of hypoxia induced by sodium nitrite and acute cerebral ischemia hypoxia are significantly prolonged, indicating thatGOPIt has a good anti hypoxia effect and has the potential to be used as a new anti hypoxia agent[22]。
2.3 Hepatoprotective activity
Alcohol is the most important risk factor for all liver diseases. Excessive or harmful alcohol intake will lead to liver injury, and then cause a series of diseases. Liu Rui et al[23-24]It is proposed to use the rat model of acute alcoholism to studyGOPThe protective effect on acute alcoholism and early liver injury was observed by recording righting reflex, detecting ethanol metabolizing enzymes and blood biochemical indicatorsGOP（ALT）, aspartate aminotransferase（AST）It can increase the activity of liver alcohol dehydrogenase, and then inhibit the increase of serum inflammatory factors caused by alcohol, suggesting thatGOPIt can protect hepatocytes and improve liver function.Wangetc.[13]The heptad of Trionyx sinensis was isolated from the traditional Chinese medicine Trionyx sinensisOC1（GAGPHGG）, studying its effects onCCl4Found during acute liver injury,sc OC1（0.34 mg/kg）Showed a higher thanigBiphenyl diester（100 mg/kg）Better hepatoprotective activity. meanwhileOC1（ALT、AST）（MDA）The formation of glutathione peroxidase increases（GSH-Px）Activity of. Simultaneous mousesc OC1LD50 of（LD50）More than6.8 mg/kg. Yang Ying[49]adoptCCl4Study on the model of acute liver injury induced by heptad isolated from turtle shellI-C-F-6（AAHGPCG）Hepatoprotective activity was found when compared with the normal groupCompared with the model group, the weights of liver and spleen were significantly increased, and the indexes of liver and spleen were significantly increased（P＜0.01）. Compared with the model group, turtle shell oligopeptide compoundsI-C-F-6The liver and spleen indexes of mice in each dose group were significantly decreased（P＜0.01）, and presented a dose-dependent manner, indicating thatI-C-F-6Be able to clearly resistCCl4The indexes of liver, spleen and thymus in mice with liver injury caused by the. I-C-F-6Can significantly reduceCCl4Serum of mice with liver injuryASTActivity（P＜0.01）. adoptCCl4Heptad induced chronic liver injury modelI-C-F-6Found during hepatoprotective activity,I-C-F-6The administration group could significantly improveSODActivity of, reduceMDAGeneration of. indicateI-C-F-6. Xushixun et al[11]Study on turtle shell oligopeptideI-C-F-6It was found during the activity of anti alcohol induced acute liver injury in mice,I-C-F-6Significantly lowerigMouse serum after alcoholALT、ASTContent and liver homogenateMDAContent（P＜0.05）, significantly elevated liver homogenateSODVitality（P＜0.05）, alleviating liver pathological damage. Thus indicating that turtle shell oligopeptideI-C-F-6It has certain preventive and protective effects on acute alcoholic liver injury in mice.
2.4 Anti inflammatory activity
Chronic and excessive inflammation can lead to many inflammatory diseases, such as atherosclerosis, rheumatoid arthritis, asthma and enteritis[57-58]. natural oligopeptides may have good anti-inflammatory potential, Wang Yinan[46]Targeting soybean OligopeptidesQRPR（Gln-Arg-Pro-Arg）Performed a series of anti-inflammatory activity evaluations and found thatQRPRCan reduce the expression of inflammatory factors; By soybean OligopeptidesQRPRActivating autophagy attenuates the inflammatory response can be found that its anti-inflammatory effect is achieved through autophagy, activatingRAW264.7Autophagy in cell models, autophagy marker proteinsLC3andBeclin1The expression increased in a dose-dependent manner; adoptMDCFluorescence staining experiments showed that,QRPRGroup showed higher fluorescence intensity and moreMDCLabeled autophagic granules. At the protein level, the final determinationQRPRFor protein kinasesB（Akt）And rapamycin target proteins（mTOR）Expression produces inhibitory effects; At the gene level, it was finally determined that with theQRPR,Akt, phosphatidylinositol-3-Hydroxykinase（PI3K）AndmTOROfmRNAThe expression was significantly down regulated, indicating thatQRPRThe mechanism of activating autophagy is that inhibition ofPI3K/AKT/mTORPathway, which provides a theoretical basis for the application of soybean active oligopeptides in anti-inflammatory. Chenqihe et al...The main reason for this is that the government has to take the responsibility for the implementation of the policy of "the government of the people's Republic of China" in the process of implementing the policy of "the government of the people[25]By using different doses ofGOPThe aqueous solution was intervened to observeGOPWhen the throat clearing effect of,GOPFor rats, the net amount of rat cotton ball granuloma and the swelling rate of toes were significantly reduced,2Description of positive test resultsGOPIt has good pharyngeal clearing function, and the mechanism of pharyngeal clearing effect is to intervene the pharyngeal inflammatory reaction, so it is presumed thatGOPIt also has anti-inflammatory activity.
2.5 Anti fatigue activity
Strengthening the anti fatigue ability of the body can improve the exercise ability of the body, Liu Na et al[45]The anti fatigue effect of soybean oligopeptide and its possible mechanism were discussed by using the exhaustion time of mice swimming to reflect the degree of exercise fatigue. The experimental data showed that medium and high doses of soybean oligopeptide could prolong the swimming time of mice, delay the occurrence time of fatigue in exercise mice, and then improve the endurance exercise ability of mice. The anti fatigue mechanism of soybean oligopeptide may be through increasing muscle glycogen in miceAnd liver glycogen reserve, maintain the blood glucose level during exercise, so as to provide more energy for the body to achieve the purpose of anti fatigue. Bao Lei et al[28]By treating mice with different doses ofGOPThe content of serum urea nitrogen and the activity of lactate dehydrogenase in mice were measured by automatic biochemical instrument, and the level of blood lactate and the content of liver glycogen in mice were detectedGOPIt has the function of relieving the fatigue degree of experimental mice.
2.6 Increase sexual activity
Sexual dysfunction is called impotence in traditional Chinese medicine, and it is believed that the erection of the penis is the result of the coordinated interaction of a series of viscera, meridians, Qi, blood and body fluid[59]According to big data statistics, there are at least hundreds of millions of men suffering from sexual dysfunction in different degrees worldwide[60]Therefore, it is particularly important to find safe and effective natural drugs to treat sexual dysfunction. Lianxiaoyuan et al[61]Ginsenosides were studiedRb1Effects on repeated stress-induced sexual deficits in male mice, it was found that before each stress30 minWith ginsenosidesRb1Treatment prevents repeated stress-induced sexual deficits and increases plasma testosterone levels, and ginsenosidesRb1The mechanism of its protective effect can be attributed to its role in maintaining normal plasma testosterone levels. Bao Lei et al[29]On this basis, male mice were treated with different doses ofGOPAqueous solution for intervention, observationGOPEffects on sexual dysfunction in mice. In continuousig 30 dAfter that, the serumNOAnd testosterone content, and it was found that theNOAnd testosterone concentrations were significantly increased; 20 minIt was found that the mating latency of mice was shortened to varying degrees and the number of mating increased, suggesting thatGOPIt can improve the sexual function of male mice.
2.7 Enhance immune function
The human immune system is a defense system for the human body to resist the invasion of pathogenic bacteria, maintain health, and avoid various diseases. Oligopeptides can be directly absorbed without digestion in human body, which is more effective than single amino acid absorption and can directly participate in protein synthesis. Interleukin in human body（interleukin）With interferon（interferon）They are peptides in the human body that can activate and regulate immune responses. Some oligopeptide fragments in traditional Chinese medicine have also been found to have immune activity. Helixia et al[30]Studied theGOPThe immunoregulatory effect on mice was observed from two aspects of specific immunity and non-specific immunityGOPThe relative mass of immune organs, cellular and humoral immune function, monocyte-Macrophage function andNK. The experimental results showed thatGOPSignificantly increased concanavalinA（ConA）Induced splenic lymphocyte proliferation ability, delayed type allergic reaction ability and humoral immune function of mice; The phagocytosis rate and phagocytic index of macrophages were found through the carbon clearance test in mice and the phagocytosis test of chicken red blood cells by mouse peritoneal macrophagesNK（P＜0.05），And the effect is better than whey protein. promptGOPBy enhancing cellular immune function, humoral immune function, mononuclear-Macrophage phagocytic capacity andNKCell activity to play a role in enhancing immunity. Lilingling et al[50]The small molecular peptides derived from Coix Seed Gliadin were explored（CPP）CPPIt can promote the proliferation of spleen lymphocytes in mice and affect the immune function of the body.
2.8 Antioxidant activity
Oxidative stress refers to that when the body is subjected to various harmful stimuli, the oxidation system and antioxidant system in the body lose balance, resulting in the damage of biological macromolecules such as tissue cells and proteins and nucleic acids, which leads to the occurrence of cardiovascular disease, diabetes, blood system disease, cancer and autoimmune disease[52-66]Therefore, it is particularly important to avoid oxidative stress and find the lead compounds with antioxidant effect. Antioxidant peptides are peptides that can inhibit the peroxidation of biomacromolecules or scavenge free radical products in the body. Ren Jinwei et al[26]Explored theGOPrightD-Effects of galactose peroxidation on Antioxidation in rats, foundGOPWith inhibition of rat liverMDAGeneration, the effect of reducing cell damage, andGOPIt can significantly reduce the levels of lipid oxidation products and protein oxidation products in rats, and significantly improve the activity of antioxidant enzymes and the content of antioxidant substances in rats（P＜0.05）And the effect is better than that of whey proteinGOPIt can enhance the antioxidant capacity of the body and has the potential as a new antioxidant agent, but the underlying mechanism of its antioxidant effect remains to be further studied and discussed. Ke Ke et al[44]The active short peptide of oyster was prepared by ultrasonic fragmentation combined with dual enzyme hydrolysis, and the scavenging rate of the active short peptide to hydroxyl radical reached22.6%, with good antioxidant activity.
2.9 Hypoglycemic activity
Diabetes mellitus is a group of endocrine diseases characterized by hyperglycemia, which is caused by insufficient insulin secretion and mainly by the metabolic disorder of fat, sugar and protein. Traditional Chinese medicine calls it "diabetes syndrome", and traditional Chinese medicine believes that ginseng can treat "diabetes syndrome". Sunbin et al[27]fromGOPStarting from, the diabetic rats with successful modeling were treated with different doses ofGOPAqueous solution for intervention to observeGOPOf hypoglycemic effect. By comparing the hypoglycemic experiment of normal animals with that of diabetic model animals, the area under the blood glucose curve at each time point after glucose administration in the two groups was observed（AUC）The changes of serum glycosylated serum protein and triacylglycerol were detected by automatic biochemical instrument（TG）, total cholesterol（TC）Serum insulin was measured by radioimmunoassay（INS）Content. The results showed thatGOPIt has little effect on fasting blood glucose of normal rats, but has no effect on insulin, glycated serum proteinTG、TC、0.5 hBlood glucose andAUCBoth have obvious downregulation, indicating thatGOPIt can obviously improve the disorder of glucose and lipid metabolism and reduce blood glucose.
2.10 Hypotensive activity
With the improvement of living standards, drinking, smoking, high salt, high sugar, high-fat diet and long-term high-pressure working environment lead to an increasing number of patients with hypertension, and hypertension is a common cardiovascular disease[67]Wanglingzhi research group[50]To explore the small molecular peptide derived from Coix Seed Gliadin under in vitro enzymatic hydrolysis conditions（CPP）In terms of biological activity in reducing blood pressure, the results showed that the final mass concentration0.1 mg/mLWhen,CPPTo angiotensin converting enzyme（ACE）The inhibition rate of was significantly higher than that of other control groups, demonstrating thatCPPIt has significant antihypertensive effect both in vivo and in vitro. Later, the members of the research group carried out the corresponding stability research[51], found thatCPPIt has high solubility and stability, providing sufficient theoretical support for further development and research of antihypertensive peptides from coix seed at home and abroad. Yuewenming[52]The antihypertensive peptide of Coix seed was prepared by biotransformation method, which also confirmed the good antihypertensive activity of Coix seed active peptide in vitro, providing a reference for the further study of antihypertensive drugs.
2.11 Antifungal activity
In recent years, due to the unreasonable application of antibiotics and hormones, as well as the widespread use of chemotherapeutic drugs and immunosuppressants after organ transplantation, the incidence of fungal infection has greatly increased, so the development of new antifungal drugs has become an important part of antifungal treatment[68]。Tianetc.[37]Isolated from the root of the golden iron lock3New cyclic peptides, i.etunicyclin B～DAnd known cyclic peptidespsammosileninB, the structure of the new cyclic peptide was elucidated by mass spectrometry and nuclear magnetic resonance analysis. In terms of activity studies, cyclic peptides were foundtunicyclin DTo Candida albicansSC5314Candida albicansY0109, Candida tropicalis, Candida parapsilosis, and Cryptococcus neoformans（BLS108）Broad spectrum antifungal activity, minimum inhibitory concentration（MIC）Respectively4.0、16.0、0.25、1.0、1.0μg/mL。
3 Conclusion and Prospect
The biological activity of oligopeptides in traditional Chinese medicine is very considerable. Oligopeptides have small relative molecular weight, strong tissue penetration, good solubility, stability, can be prepared in large quantities, and the oral or injection effect is ideal, and the immunogenicity is poor. Therefore, this absorption advantage of oligopeptides has great potential medicinal value. It has shown good biological activities in anti coagulation, anti hypoxia, liver protection, anti-inflammatory, anti fatigue, improving sexual function, antioxidation, enhancing immunity, reducing blood pressure, blood glucose, antifungal and other aspects. According to a large number of literatures, the author summarizes3To speculate the activity of natural active oligopeptides in traditional Chinese medicine, and then provide new methods and ideas for the development of new drugs of active oligopeptides in traditional Chinese medicine.
3.1 Inferring the bioactivity of oligopeptides from the classification of traditional Chinese Medicine
According to the comparative analysis of the clinical efficacy classification and bioactivity of natural oligopeptides, we can speculate the relationship between the classification attributes of traditional Chinese medicine and the bioactivity of oligopeptides. For example, Sparganium and Hirudo belong to the drugs of activating blood circulation and removing blood stasis. The cyclic dipeptide in Sparganium and Hirudo oligopeptide show good anticoagulant activity; Ginseng and turtle shell are both tonic drugs,GOP; Because the oyster peptides in oysters have antioxidant activity, it can be speculated that scallop oligopeptides in scallops, which are also liver calming and wind calming drugs（SPs）It also has antioxidant activity.
3.2 Inferring the bioactivity of oligopeptide components from the main pharmacodynamic functions of traditional Chinese Medicine
Li Wen et al[34]In order to explore the material basis for gecko to exert its pharmacodynamic effect, it was isolated from gecko4Cyclic dipeptides, i.e., cyclic (proline-Leucine)[cyclo-(Pro-Leu)], loop (alanine-Proline)[cyclo-(Ala-Pro)], loop (Glycine-Proline)[cyclo-(Gly-Pro)], loop (alanine-Valine)[cyclo-(Ala-Val)]In recent years, clinical research on gecko has found that gecko can be widely used to treat gastric cancer, esophageal cancer, liver cancer and other cancers, but there are few reports on the chemical composition. The author speculates that gecko isolated from4Cyclic dipeptides may have better antitumor activity.
3.3 Enhancing the bioactivity of oligopeptides by modifying their sequences
Tobacco bacterial wilt is a major disease in tobacco production, jiangshilong et al[69]In order to solve the problem of controlling tobacco bacterial wilt, cecropin（cecropin）By modifying the cecropin peptide sequence, we designed5Species of oligopeptides, and the bacteriostatic activity was determined by the bacteriostatic circle assay, and the result number was228Oligopeptide of（WKLFKKILKYL）It has the best effect and is expected to become a new biological control agent of bacterial wilt. Earthworms in their unique living environment, after a long time of evolutionary adaptation, formed a defense microbial mechanism and antibacterial spectrum different from other organisms. It can be seen that the modified natural oligopeptides may have better biological activities.
It is suggested that researchers should test the activity of the reported oligopeptide components in traditional Chinese medicine, and enhance the biological activity through peptide sequence modification, further enrich the natural product oligopeptide library, which has important theoretical value and practical significance for the in-depth research and development of oligopeptide rich traditional Chinese medicine, and has certain reference significance for the modernization and internationalization of traditional Chinese medicine.