INTRODUCTION

In recent decades, the variety of drugs based on peptides and proteins has increased significantly as a result of the intensive development of biotechnology and genetic engineering. If in the 1980s, when the real development of the peptide industry began, approximately 5 new peptide-based molecules entered clinical trials annually, in the 1990s this index was 10 molecules per year. Nowadays, about 20 new peptides are studied each year and, on average, three are registered as a new drug. By 2013, there were over 400 types of these drugs.

Peptide compounds are conventionally subdivided into oligopeptides (up to 50 amino acids), peptides (50–100 amino acids), and proteins (more than 100 amino acids). Proteins can be simple (contain only amino acids) or complex (in addition to amino acids, they can contain various organic or inorganic compounds). Recently, much attention has been paid to the study of the properties of low molecular weight peptides as drugs (Table 1). These compounds penetrate freely through the BBB (blood–brain barrier), have a multifaceted effect on the central nervous system (central nervous system), and are highly effective provided that they are in very low concentrations in the body. A brief review of peptide drugs used in the Russian Federation showed that at least one third of them are oligopeptides.

Table 1. RPs and their analogs
Full size table

PHYSIOLOGICAL AND PHARMACOLOGICAL PROPERTIES OF REGULATORY PEPTIDES

In 1970s, the nootropic and neurotransmitter properties of vasopressin and ACTH were identified. Later, hundreds of neuropeptides with a wide variety of functions were discovered in the brain. It turned out that these oligopeptides accelerate the recovery of damaged nerves and the maturation of the neuromuscular system, have anti-inflammatory and antipyretic effects, affect pain sensitivity, regulate the functioning of the CVS (cardiovascular system), model behavioral responses, etc. Subsequently, similar compounds were found in the periphery [1–3]. They are collectively called regulatory peptides. It should be noted that almost all RPs (regulatory peptides) belong to the oligopeptide class but not all oligopeptides have considerable biological activity.

Thus, RPs are a group of biologically active substances of peptide nature. Their main features are: polyfunctionality, a cascade mechanism of action, and formation from a precursor polypeptide. RPs perform important neurotransmitter, modulatory and integrative functions, and form a single functional continuum, being a link between the main information systems (nervous, endocrine, immune). Their importance increases when the body is exposed to negative factors (stress, damage, etc.) [1, 3–6].

Currently, more than 10000 RPs are known (in 1991, this number was a little over 300). Structurally, they are distinguished by the small size of the molecule (for the overwhelming majority of 2–20 amino acid residues). This allows many of them to pass histohematogenous barriers and affect certain brain structures, a number of endocrine organs, and the lens [1, 7–10]. In the central nervous system, the RPs are called neuropeptides. They act as mediators and, participating in the feedback inhibition of neurons, act as modulators of various processes, creating interneuronal connections. Peptides can be not only short-term mediators of chemical transmission, but also long-term regulators of membrane properties and synaptic action. Their effect on neuronal activity is often expressed in changes in behavioral responses [11–13].

One of the main mechanisms of RP formation in vivo is post ribosomal processing, in which they are cleaved from physiologically inactive precursor proteins using specific non-lysosomal peptide hydrolases [3]. Quite often, a whole group of peptides appears from one precursor protein, which is necessary for successful adaptation to certain changes in the environment [12, 14, 15].

Another source of RP formation is limited proteolysis from physiologically active proteins (cytokines, thymus peptides, immunoglobulins, etc.). In this case, the short peptide is often many times superior in activity (albeit in a different region) to the precursor peptide, has higher affinity, and lacks species specificity and immunogenicity [2, 3, 16].

The RP system takes part in the regulation of almost all physiological reactions of the body, maintaining the vital balance (homeostasis) of all its systems. A characteristic feature of RPs is polyfunctionality of most of them, i.e. the ability of each compound to influence several physiological functions.

The mechanism of polyfunctional physiological influence on body functions in RPs is quite complex and is determined by two types of action: (1) optional action, this is interaction with membrane structures (various types of receptors, ion channels, etc.), leading to a change in the functional activity of the cell, including changes in the genomic response; (2) obligatory action, the formation of a peptide cascade. In the overwhelming majority of cases, both mechanisms of action are combined, however, the pharmacological properties of RP are often determined by the formation of cascade processes.

Interaction with membrane structures depends on the specific features of the chemical structure of the RP: the molecules, as a rule, have several ligand binding groups intended for different cellular receptors. Depending on the place of release, RPs can exert or modulate the mediator function, stimulate or inhibit the release of hormones, regulate tissue metabolism, and perform the function of an effector molecule. The second characteristic feature of peptide regulation is that many RPs of various structures can induce unidirectional changes in specific physiological functions of the body. Thus, several RPs can act on the same target, while the same modulator can act on several targets at once. Due to this, various combinations of modulators and various combinations of target cells can be created. Each combination corresponds to a certain functional state of the nervous system and the body as a whole [10, 11]. Due to the numerous peptides and their continuous formation, a functional continuum is formed, where one combination of RP combinations smoothly turns into another, that more appropriate at a given moment for the functioning of the body.

The modulatory effect of neuropeptides on the activity of the central nervous system is largely associated with their effect on monoaminergic processes and depends on the ratio of the activity of the dopamine, norepinephrine, and serotonergic systems of the brain [17–19]. The modulating effect of RP on neurotransmitter processes in the brain is defined as a regulatory effect that may not manifest itself against the background of optimal functioning of physiological or biochemical systems. However, when the functional state of neurotransmitter systems, in particular, monoaminergic systems is shifted, the corrective effect of peptides on the central nervous system manifests itself quite strongly [17].

The target of RP action, leading to positive therapeutic effects, may be not only receptor systems but also directed change in the transcriptome by changing the activity of certain genes. Interaction of oligopeptides with the cell membrane leads to signal transmission to the cell nucleus, the activation of early transcription factors, and a change in the activity of the transcriptome and proteome (protein biosynthesis) of the cell, which ultimately changes the functional state of cell structures [2, 16, 20–22].

However, the main mechanism for the formation of the functional continuum of RPs is a cascade process. It is known that any change in homeostasis leads to the formation and release of RPs, which not only interact with certain receptors of target cells, changing the parameters of their functioning, but also induce the release of the next group of regulatory agents from these cells. The released RPs act on their target cells, causing both changes in metabolism and the release of the next group of the peptide cascade. Thus, the primary effects of RPs can develop over time in the form of a cascade process and, despite the fact that the RP itself is rapidly (within minutes) destroyed in the body, its physiological effect can last for a long (hours–day) time [9, 12, 13, 23]. Dysfunction of the peptide cascade can be described by the concept of “pre-disease”, when a dysfunction occurs with the structural components remaining intact. In this case, there is a breakdown of cascade processes, which largely determines the pathogenesis of the disease.

The biological meaning of the existence of long-term regulatory processes, consisting of short-term links, is obvious. Unlike systems based on long-lived regulators, such a system is more flexible in the face of permanently changing information about the states of the internal and external environment. For a quick (within seconds) release of RP, cells contain “semi-finished products” in the form of inactive protein precursor molecules, from which, using protease enzymes, the required number of various RPs is quickly cleaved, depending on the body’s needs. The precursor protein itself does not have the activity of the peptides included in its structure, but if necessary, it is possible to quickly (hundreds of times faster than by ribosomal synthesis) obtain the products the body needs from it. This process is called intracellular processing [14, 15, 24]. Thus, depending on the nature of the pathological effect, the same RP in the same cells is able to induce the release of various endogenous regulators.

It has been established that all cells of the body constantly synthesize and maintain a functionally necessary level of RPs (i.e., activity of functional continuum at a certain point in time), but, in the case of a disturbance of homeostasis, RP biosynthesis either increases or decreases. These fluctuations occur during adaptive reactions and physical or emotional stress and under conditions of pre-disease preventing the disruption of the functional balance. If the disease is formed or there is pronounced intoxication, then the functioning of the RP system is suppressed and cascade processes become destructed [3, 25].

CHARACTERISTICS OF A NEW CLASS OF MEDICATIONS—RP ANALOGS

RPs can induce the cascade physiological phenomenon which makes it promising to create a new class of innovative drugs, RP analogs based on them (Table 1). The important advantages of RP analogs over the original molecules will be:

(1) product de novo; in the organs and tissues of the body, RPs are present in microscopic quantities, so, instead of extraction from living material for the needs of medical practice, they are synthesized. This determines the accuracy of their dosage and the possibility of pharmacokinetic studies (in contrast to hydrolysates and other tissue extracts);

(2) high efficiency at small and ultra-low doses; for regulation of the physiological functions, RPs are released at microscopic concentrations, which determines their low dosage (as a rule, tens to hundreds of micrograms);

(3) lack of pronounced adverse side effects (including allergic reactions); the therapeutic effect of RP is based on the principle of recovery of natural regulatory processes disturbed by the disease, i.e., there is a kind of “ceiling effect” which is the restoration of the normal reaction of a certain tissue or organ, and a further increase in the effect is absent;

(4) extremely low toxicity; the degradation products of RP analogs are natural amino acids;

(5) complexity of action; a characteristic feature of RP analogs is that most of them have polyfunctionality. This is related both to the chemical structure of drugs (their molecule, as a rule, has several ligand binding groups intended for different cellular receptors) and to the initiation of peptide cascades. In the latter case, the cells participating in the cascade begin to produce a variety of biologically active substances (hormones, mediators, modulators, etc.), the physiological effect of which is formally attributed to the RP or its analog, which triggered this process. An important point in the use of RPs is their ability to normalize the level of tissue trophic factors (for example, in the brain tissue). The latter, in turn, inhibits various mechanisms of the pathological cascade and stimulates reparative processes [22];

(6) individuality of action; being analogs of the body’s own bioregulators, RPs restore the functioning of only those functional systems (peptide cascades) that are impaired in this particular person in this particular situation. In clinics, people with the same disease often have different variants of its time course. This will determine the difference in the therapeutic effects of the RP analog in different patients with the same diagnosis;

(7) duration of action; RP analogs will exist in the body for a short time and become the initial link in the chain of cascade reactions, so their physiological effect can last for a long (hours-day) time [1, 10, 12, 23];

(8) duration of residual effect; promoting the normal functioning of cascade processes in body tissues, RP analogs also restore the natural self-regulation, which was impaired as a result of adverse factors or the development of pathology [1, 10, 12, 23]. The average time of drug administration is 14 days. Further, depending on the nature and severity of the disease, the therapeutic residual effect of RP analogs after the withdrawal of the drug is observed for another 3–6 months, which dictates the duration of the interval between courses of therapy in the treatment of chronic diseases. The duration of the therapy and therapeutic residual effect depend on the timing of the restoration of the peptide cascade, achievement of its “full capacity” and the duration of its functioning without further support [10, 17, 20, 23].

While such aspects of therapeutic use as high efficiency at low and ultra-low doses, lack of pronounced adverse side effects, low toxicity, complexity, and long duration of action can still occur in different groups of drugs, the individuality of action and long-term residual effect are characteristic only for the RP analogs, since they are associated with their ability to “reanimate” cascade processes.

One of the main disadvantages of oligopeptide therapy (with the exception of most di- and tripeptides) is the rapid degradation of drugs by endogenous proteases. For example, analogs of ACTH4–10 Ebiratid and Org 31433 have a half-life of only about a minute [26]. The main ways to correct this drawback are:

(1) replacement of terminal L-amino acids with D‑amino acids (ORG 2766) or additional introduction of a non-amino acid radical (oleylcarnitine) into the terminal part of the molecule. However, in this case, a change in the properties of the drug may occur in the direction of increased toxicity. In particular, accumulation of unnatural D-amino acids in the aging body may cause malignant neoplasms [27, 28];

(2) attachment to the molecule of amino acid combinations, most often containing proline, for example the Pro-Gly-Pro tripeptide. In this case, it can also be expected that the hydrolysis of the primary structure of these oligopeptides by endopeptidases will produce active fragments that prolong the effect of the drug [1, 29, 30];

(3) cross-linking of oligopeptides with carrier proteins. However, when analyzing the biological activity of free RPs and their artificially synthesized complexes with carrier proteins (using the example of vasoactive and opioid peptides), it was found that PPC (protein-peptide complex), as compared with native RPs, are characterized by an expansion of the activity spectra, i.e. as a result, a drug with other unplanned properties may be obtained [31].

An important point is that a number of oligopeptides have their own unique route of administration into the body—through the nasal mucosa. This intranasal route of administration is an alternative to traditional delivery methods and has a number of advantages: rapid development of the therapeutic effect, the absence of the aspect of the first passage of substances through the hepatic barrier (“first passage” effect), the ability to deliver drugs directly to the central nervous system, high bioavailability, as well as convenience and ease of use [32].

It is the ability to deliver drugs directly to the central nervous system that is the most important feature and advantage of the intranasal route of administration: the transport of drugs from the nasal cavity directly to the central nervous system is performed using perineural transport through the olfactory and trigeminal nerves, bypassing the BBB (the olfactory bulb is practically devoid of it) [29, 32].

RP ANALOGS IN THE PRACTICE OF EXPERIMENTAL AND CLINICAL MEDICINE

Specificity and safety of drugs is the main problem for pharmacology, and from this point of view, RP analogs are of great interest [20]. The creation of their synthetic analogs can be a breakthrough in the treatment of acute and chronic diseases [3, 33]. However, despite the efforts of pharmacologists, there are few drugs based on oligopeptides. This is due to their polyfunctionality, rapid degradation by various proteases, and the complexity and ambiguity of their mechanism of action [20]. The promising synthesis of RP analogs is based on the concept of targeted design of peptides with certain physiological properties, which is based on the use of the structure of native RPs with a known effect [34, 35].

At present, drugs based on RPs have begun to be actively used in medical practice.

Neurology. One of the most important problems in neurology is acute and chronic cerebrovascular diseases: 5–7 million people die from stroke in the world every year, about the same number of people become disabled. CCVD (chronic cerebrovascular disease) is a progressive disease leading to a decrease in life expectancy, earlier disability and significant cognitive impairment. The use of RPs (heptapeptides Semax and Deltaran, dipeptide carnosine, tetrapeptide cortagen) in the treatment of acute cerebrovascular insufficiency (ACVI) leads to a decrease in mortality in both ischemic and hemorrhagic strokes, stabilizes and significantly slows down CCVD progression and reduces the likelihood of complications (stroke, transient ischemic attack (TIA)) [27, 36–40]. Thus, the early use of Semax in severe stroke reduces the mortality and disability of patients by 4 times, and its use for the treatment of discirculatory encephalopathy stabilizes the clinical course of the disease and reduces the possibility of development of strokes and TIA by 2–2.5 times [41–43].

TBI (Traumatic Brain Injury) has enormous socioeconomic implications because more than 10 million people worldwide are diagnosed with it every year and it is associated with high rates of hospitalization, death, and disability. Modern therapy does not always lead to satisfactory results. One of the causes is the complexity of the pathogenesis of secondary brain damage. The use of oligopeptide drugs (Semax, BPC 157) leads to a decrease in mortality (up to 3 times), a decrease in the degree of disability and the duration of hospitalization by 30%, and in the long term it accelerates the rehabilitation and socialization of patients [44–47].

The problem of restoring the functioning of peripheral nerves is also important. Thus, the use of GAL-1 promotes regeneration of axons after peripheral nerve trauma [48].

Moderate cognitive impairment in people over 60 years old occurs in about one in six, and the risk of developing dementia within 5 years is more than 50%. The main causes of cognitive impairment are vascular and neurodegenerative pathologies. For the treatment of cognitive disorders, neuropeptides based on ACTH (Ebiratid, Semax, Org 31433) and N-phenylacetyl-L-prolylglycine ethyl ester dipeptide (Noopept) have been used with success [20, 26]. RP drugs are more active in vascular disorders: in this pathology, cognitive activity can be improved in more than 80% of patients [42, 49, 50].

Psychiatry. A complex neural network involving the peptidergic signaling pathway underlies the development of a complex of physiological behavior and is closely related to social behavior and emotions [51, 52]. Disruption of peptidergic connections alters the exchange of neurotransmitters in the mesolimbic system of the brain, which underlies the pathogenesis of all major mental diseases. This is especially pronounced in borderline states and, above all, in the initial stages of anxiety disorders, depression, and neurasthenia. Usually, psychoemotional disorders are treated with tranquilizers (anxiety) and antidepressants (depression and subdepression) and, in some cases, drugs with psychoactivating effects (asthenia, neurasthenia) and nootropics (cognitive disorders) are used. One of the main unresolved problems in the treatment of psycho-emotional disorders is that most patients have a combination of these disorders, which requires the use of a set of psychotropic drugs of different classes. However, the vast majority of them have a variety of adverse effects (including drug dependence and withdrawal symptoms, organ-specific toxicity, and adverse effects on behavioral responses and cognitive functions) and significant drug-drug interactions [53, 54]. The way out of this situation is the use of safe drugs with a combined action. These properties are possessed by the oligopeptide drugs deltaran, cortagen, and selank; among them, the latter is most widely used in clinics. Selank is a heptapeptide, the structure of which is based on the tetrapeptide taftcin. The spectrum of psychotropic activity of this drug is unique—it is an anxiolytic with an antidepressant effect, antiasthenic effect, and an activating effect on mnestic and cognitive functions [28, 55]. Thus, the oligopeptide selank can replace at least four groups of psychotropic drugs at once: tranquilizers, antidepressants, nootropics, and antiasthenic drugs.

The anxiolytic and antidepressant effect of Selank is related to the regulation of the synthesis and metabolism of norepinephrine, serotonin, and enkephalins in the emotiogenic zones of the brain at the genome level [53, 55–60]. The drug reduces the behavioral manifestations of anxiety and depression without the side effects typical of most common anxiolytics (muscle relaxation, sedation, drowsiness, drug dependence, withdrawal syndrome, etc.). At the same time, its anxiolytic effect is comparable to the effect of widely used tranquilizers (phenazepam, diazepam, medazepam) [53, 54, 61]. The antiasthenic effect of selank is associated with the regulation of dopamine synthesis, and the nootropic effect is associated with an increase in neuroplastic and neurotrophic effects in the central nervous system [60].

Narcology. The role of peptidergic systems, in particular the opiate system, in the formation of dependence on chemical agents is unquestionable. The development of drug and substance abuse is associated with both quantitative and qualitative changes in the composition of brain oligopeptides, which is one of the main links in the pathogenesis of addiction. At the same time, the real effectiveness of drug therapy for various drug addictions is not very encouraging [62]. The administration of RP analogs to patients can become the basis on which the subsequent treatment of drug addiction will be built. This is confirmed by data from experimental and clinical studies. Thus, when toxic doses of ethanol are administered to animals, Semax and Selank reduce its toxicity by 40%, and, during withdrawal syndrome, they normalize the individual behavior of white rats, restoring anxiety and depression indices to the level of intact animals, activate their sociability, and have an anti-aggressive effect. One of the causes of this is the restoration of indices of dopamine and serotonin metabolism in the central nervous system of animals [63, 64].

The use of Semax in clinics increases the tolerance of high doses of ethanol, reduces mortality in acute alcohol poisoning (4.5–8 times in relation to basic therapy), increases the tolerance of withdrawal symptoms, reduces (by 3 times in relation to basic therapy) the likelihood of development of delirium [65, 66]. The use of Selank for the treatment of heroin addiction leads to the normalization of the level of β-endorphin and enkephalins in the blood, which contributes to a substantial improvement in the condition of patients with withdrawal syndrome. When used together with benzodiazepines (phenazepam), Selank eliminates the side effects of drugs and the severity of the withdrawal syndrome [54, 61, 67].

The cardiovascular system. According to experimental and clinical data, RPs affect all links of the structural organization of the CVS. These effects are practically unnoticeable under normal conditions (the state of rest of a healthy person) but may be observed in case of pathological or excessive load to the body [63]. Thus, the use of RP analogs (glyprolines, modified opiates) in experiment and clinics [1, 36, 37, 57, 68–71]:

(1) helps to normalize blood pressure while reducing the dose of basic drugs (ACE inhibitors), ATP blockers, β-blockers, anticalcium drugs, diuretics);

(2) has a cardioprotective effect in the form of normalization of heart rate, antiarrhythmic effect, prevention of hypertrophy and apoptosis of cardiomyocytes, increased survival of cardiomyocytes in ischemic conditions, and stimulation of reparative processes in myocardial infarction;

(3) promotes the normalization of regional blood flow and microcirculation under stress and chronic pathology in the form of improvement of cerebral hemodynamics, modulation of impaired blood circulation, and protection of the digestive system and the walls of large vessels from stress.

One of the main mechanisms of this influence is the regulation of the activity of the systems of endogenous opiates (primarily enkephalins), monoamines (catecholamines, histamine, serotonin), and corticosteroids in stress and chronic pathology [57, 69, 71, 72]. A number of RP analogs (vesugen, D7, Semax, BPC 157) in the elderly have vasoprotective effects, which are related to the expression of Ki67 protein genes [73–76].

Oligopeptides (glyprolines, BPC 157) play an important role in the regulation of the mechanisms of hemostasis. They can interact with high molecular weight heparin with the formation of a complex compound, which, under conditions of hypercoagulation, promotes anticoagulant and fibrinolytic actions both in vitro and in vivo. In addition, under conditions of pathological influences, there is a beneficial effect on the physiological activity of platelets, preventing aggregation [77, 78].

In recent years, it was shown that glyprolines (primarily, the tetrapeptide glypropol) have a positive effect on the probability of occurrence of risk factors for cardiovascular diseases typical of metabolic syndrome such as increased blood glucose, triglycerides, total cholesterol and low density lipoproteins, obesity, increased pressure, and platelet adhesion [20, 79, 80].

Digestive system. The use of oligopeptides can be viewed as a promising new approach to the prevention and treatment of gastrointestinal disorders. The mechanisms of their gastroprotective effect are different and are mediated by the regulation of gene expression, DNA replication, and protein biosynthesis. They have an antioxidant effect, modulate the activity of hormones and enzymes, vascular permeability, and neoangiogenesis, have neuro- and immunomodulatory effects, and affect motility, secretion and regeneration of the gastric mucosa [81].

In the treatment of stomach diseases (gastritis, peptic ulcer, reflux disease), oligopeptides are widely used. The most studied representatives of oligopeptides with gastroprotective properties are met-enkephalin, an analogue of Leu-enkephalin dalargin, dermorphin, sedatin, BPC 157, proline- and hydroxyproline-containing collagen degradation products (mainly Pro-Gy-Pro, Gy-Pro and Pro-Gy ), thymohexin, honluten (T-34), vesugen (T-38) [4, 81–88].

Gastric pentadecapeptide BPC 157 is resistant to gastric juice, and regulates the functions of both the cardiac sphincter and the pylorus. It is recommended for use as an antidote with NSAIDs (non-steroidal anti-inflammatory drugs) in cases of gastrointestinal (gastrointestinal) tract damage. BPC 157 also has a beneficial effect on the functional state of the duodenum, small and large intestine, and liver [86, 89].

The dipeptide L-carnosine (used in Japan as an antiulcer drug for about two decades) has a gastroprotective effect by increasing the formation of protective mucus and antioxidant properties [90]. The tetrapeptide epitalon restores physiological regulation of the pyloric part of the stomach and has a positive effect on the body’s adaptive reactions [91]. The oligopeptide sedatin reduces erosive and ulcerative gastric lesions caused by NSAIDs and promotes DNA synthesis in the epithelium of the gastric mucosa [81]. The hexapeptide thymohexin (immunophan) is a fragment of the hormone thymopoietin at position 32–37. Thymohexin has a very broad biological effect: it stimulates the proliferation and maturation of T-lymphocytes, increases the phagocytic activity of polymorphonuclear granulocytes and macrophages, increases the production of antibodies, and modulates the activity of ATP-dependent transport membrane proteins. Thymohexin also has significant antioxidant and anti-inflammatory effects. The latter is mediated by its inhibitory effect on the synthesis of TNF-α (tumor necrosis factor-alpha) and some other pro-inflammatory cytokines [92]. Tripeptide vesugen increases proliferative processes in the tissues of the gastrointestinal tract, which is associated with its positive effect on blood vessels. This leads to an improvement in tissue trophism and stimulation of cell proliferation [2]. The tripeptide honluten (T-34) has an anti-apoptotic effect on cultured epithelial cells of the human stomach and is able to stimulate protein biosynthesis [93].

Of the glyprolines, Pro-Gly-Pro, Pro-Gly-Pro-Pro, and Gly-Pro had the highest antiulcerogenic action. The gastroprotective effect of glyprolines can be explained by the anti-inflammatory effect of these substances, their participation in the regulation of acid and bicarbonate secretion and an increase in the synthesis of structural proteins, including collagen [81].

Some short peptides are resistant to gastric and intestinal proteinases, which allows them to be administered orally to a patient. These properties are possessed by livagen, glyproline (Gly-Pro-Gly) and BPC 157 [86, 88].

Synthetic oligopeptides associated with the primary structure of hCG (human chorionic gonadotropin) are used as highly effective hepatoprotectors. They have anti-inflammatory effects, antioxidant effects, and prevent neutrophilic infiltration in the liver, which leads to a decrease in the level of liver damage [94]. The heptapeptides Semax, Selank and Pro-Gly-Pro tripeptide have pronounced hepatoprotective activity.

Kidney function. Oligopeptides (3 to 7 amino acids) derived from the beta subunit of chorionic gonadotropin and selank contribute to the normalization of organ function in cases of kidney lesion (renal failure, nephrectomy) [34, 95].

The immune system. There is an idea that oligopeptides can perform their functions at the level of intercellular interaction between the genomes of various structural and functional elements of neuroimmunoendocrine regulation, which determines their immunomodulatory effect [96]. Selank and its fragments have a regulatory effect on the expression of the Bcl6 gene, which plays a leading role in the formation and development of the immune system; in particular, its activity contributes to the differentiation and survival of lymphocytes and macrophages, and it also participates in the control of the cell cycle [97–99].

Clinical studies have shown the INT-inducing effect of Selank: it increases the synthesis of INT-α (interferon) and prevents the blockade of the synthesis of INT-γ, regulates cell-mediated and humoral immune responses, and maintains the functional activity of granulocytes [100–102]. Semax has a similar effect [101].

Another example is the oligopeptide specific stimulator of cellular immunity, designed to combat mycoplasma infection [103].

Infectious diseases. Oligopeptides are increasingly used in the treatment of infectious diseases. This is due to both their immunomodulatory activity and their own antimicrobial action. The influence on the interferon system can explain the antiviral effects of Selank and Semax: they are effective in the emergency prevention of influenza A (H3N2), herpes simplex virus types 1 and 2 (HSV-1,2), and cytomegalovirus infection [101, 104, 105]. Oligopeptide blockers of matrix metalloproteinases, which suppress the vital activity of microorganisms [103], oligopeptides that inhibit the replication of the respiratory syncytial virus [106] and retrovirus [107], as well as oligopeptides that promote the synthesis and release of protective molecules (due to modulation of gene expression in the cell) have been synthesized [108].

Oncology. The results of recent studies indicate the indisputable and significant participation of certain RPs in the suppression of malignant growth. Thus, the inhibition of tumor development is facilitated by many RP analogs with immunomodulatory activity [96]. Another mechanism of antitumor action is possessed by oligopeptides that inhibit tumor angiogenesis due to blockade of metalloproteinases. Tissue inhibitors of metalloproteinases prevent the switch of tumor development to an angiogenic phenotype, which delays its growth and metastasis [3, 109]. Ligand YC21 (an oligopeptide of 21 amino acids) inhibits cell proliferation in positive malignant liver tumors by blocking the activity of mitogen-activated protein kinase [110]. Oligopeptides (containing 3–7 amino acids) obtained from the beta-subunit of chorionic gonadotropin also have antitumor activity [34].

Endocrinology. Many peptide hormones are oligopeptides. An example of RPs acting in the central nervous system and in the periphery is vasopressin and oxytocin, which are involved in the pathogenesis of anxiety, depression, aggressiveness, attention deficit hyperactivity disorder, post-traumatic stress disorder, autism, bipolar disorder, and pain management. On the periphery, vasopressin, in addition to regulating diuresis, is involved in glycogen metabolism, platelet aggregation, vascular proliferation of smooth muscle cells, regulation of functions and motility of the gastrointestinal tract, uterus, and bronchi, and natriuresis in the kidneys [111–113]. Oligopeptides that antagonize vasopressin action were created: Manning peptides that work only in the brain [111].

For a long time, attempts have been made to create synthetic oligopeptides that regulate the intensity of synthesis and secretion and tissue effects of hormones. One of the first drugs in this group was deamino-arginine-vasopressin, created for the treatment of diabetes insipidus. In recent decades, drugs for the treatment of diabetes mellitus have been actively developed. Thus, oligopeptides that suppress the development of type I diabetes were obtained from the β-subunit of chorionic gonadotropin [34]. The tetrapeptide glypropol prevents the development of type II diabetes mellitus [20], and peptides of the glyproline series (Pro-Gly-Pro, Pro-Gly, Semax, Selank) additionally ensure the maintenance of the normal function of the body’s insular system [78].

Ophthalmology. Retinal neurons are phylo- and ontogenetically derived from brain neurons, therefore, the dynamics of pathological processes occurring in retinal neurons and optic nerve fibers during hypoxic-ischemic disorders is similar in nature to damage of cerebral neurons of vascular genesis [75]. This predetermined the use of neuroprotective drugs in ophthalmology, including oligopeptides [114]. The first object of research was Semax, which is currently successfully used for the treatment of glaucoma, retinopathies (including diabetic), neuritis and optic nerve atrophy [73, 114–118]. The tripeptide progluprol is intended for the treatment of diabetic retinopathy. The oligopeptide ALG-1001, which is proposed for the treatment of dry and wet macular degeneration, diabetic macular edema and symptomatic vitreomacular adhesion, is undergoing clinical trials. The oligopeptide squalamine (used intravenously and in the form of eye drops) is an inhibitor of vascular growth factors (VEGF (vascular endothelial growth factor), and PDGF (platelet growth factor)), which prevents pathological angiogenesis in the retina. This allows it to be used in the treatment of wet macular degeneration and diabetic retinopathy [119].

Dermatology. Over the past decade, Semax has been successfully used to treat psoriasis, exudative diathesis, and acne; its possible therapeutic mechanisms of action are regulation of the synthesis and release of trophic factors, immunomodulatory and anti-inflammatory effects, and improvement of tissue microcirculation [120, 121]. Positive results in the therapy of melasma were obtained after the use of the oligopeptide “Lumixyl”, a competitive inhibitor of tyrosinase, which inhibits the synthesis and decreases the content of melanin in melanocytes. The drug has low toxicity, is used in short courses (7 days), and has an effect even in severe disease [122].

Prenatal and early neonatal periods. These periods of life play an important role in the development and formation of neurophysiological mechanisms and mental functions. In turn, stress factors (including drugs of central action: antidepressants, tranquilizers, antipsychotics, etc.) that affect the fetus/child during these periods may in the future provoke the development of mental pathology (anxiety, depression) and worsen the learning abilities. Considering the high safety of RP analogs, their absence of fetotoxicity and harmful effects on the infant, it is possible to use them in the prenatal and early neonatal periods of life for the correction of hypoxic-ischemic disorders, stressful situations, and drug behavioral toxicity [20]. The inclusion of Semax in the complex of rehabilitation therapy in children of the first week–first month of life with perinatal hypoxic-ischemic brain damage promotes a decrease in the level of destructive processes in the central nervous system, determines significant positive dynamics of the neurological picture and increases the recovery rate of disturbed parameters of psychomotor development of children [123, 124].

Fertility. Studies have shown that Semax has an activating effect on sperm motility, especially on the active fraction in the first hours after exposure. This drug can be recommended for use as a substance that improves ejaculate fertility in programs of assisted reproductive technologies, given the lack of embryotoxicity and mutagenic properties of the drug [125].

Inflammatory processes. Inflammation is a common pathophysiological reaction that plays a significant (and often decisive) role in the pathogenesis of most human diseases. This determines the importance of the development of safe and effective anti-inflammatory drugs. Although the drugs used today (glucocorticoids, NSAIDs, a number of cytokines and their antagonists) have a pronounced anti-inflammatory effect, they are not safe and have numerous (and in some cases fatal) undesirable effects. Oligopeptides, as drugs with a high degree of safety, can become a good alternative to modern anti-inflammatory drugs. Currently, there are many peptide anti-inflammatory drugs of various structures and different origins: oligopeptides derived from chorionic gonadotropin (LQGV, AQGV, and LAGV), BPC 157, thymohexin, vesugen, RP of the glyproline family (glyprolol, semax, selank), and many others [34, 94, 97, 126].

The mechanism of anti-inflammatory activity of oligopeptides differs in basic parameters from glucocorticoids and NSAIDs and is associated with the regulation of the cell transcriptome, which decreases the synthesis of pro-inflammatory agents (TNF-α, and IL-6 (interleukin), IL-1β, E-selectin, a number of other cyto- and chemokines, products of free radical oxidation), while anti-inflammatory (TGF-β1 (transforming growth factor), IL-10, and a number of other cyto- and chemokines, on the contrary, increases [92, 94, 96–98, 126].

Adaptation. One of the main properties of the body is adaptation, i.e., the ability to change its reactivity in accordance with the constant changes in the conditions of the internal and external environment. An increase in the adaptive capabilities of a subject to the damaging factors of the external and internal environment is one of the ways to increase life expectancy and a mechanism for preventing diseases and pathological conditions and increasing survival and working capacity in difficult natural conditions. It is possible to increase the body resistance with the help of drugs of various groups including the analogs of RPs, which have a regulatory and restorative effect on body functions [20]. Oligopeptides (AQGV, Semax, Selank, Glypropol, Progluprol, Cortagen, Carnosine, Pinealon, Vesugen, Vilon, Dilept, Epitalon) increase physical and mental performance, protect the body from extreme muscular loads, hypoxia, stress of various etiologies, hypo- and hyperthermia, radiation, and the toxic effects of chemical agents [3, 34, 72, 86, 95, 96, 127].

It has been found that many RPs promote an increase in life expectancy. One of the mechanisms for this is their antioxidant activity. Oligopeptides (carnosine, pinealon, vesugen, etc.) are able to correct disorders at the level of intercellular interaction between the genomes of various structural and functional elements of neuroimmunoendocrine regulation under conditions of oxidative stress that occurs during aging due to the development of various pathological processes (cardiovascular diseases, impaired cerebral circulation, malignant growth, neurodegenerative diseases) [96]. A different mechanism of the gerontoprotective effect was revealed for vesugen and D7 oligopeptides. In the elderly, they have a vasoprotective effect, which is associated with the expression of genes for the Ki67 protein, whose synthesis decreases with age [76].

CONCLUSIONS

Summarizing the above, it can be noted that the entire functional continuum of RPs is a unique basis for the development of new pharmacologically important drugs. Their native structures, minimal side effects, and high physiological activity at low doses provide a practically win-win molecular “template” for creating medicinal agents. It should be noted once again that the main target of the action of RP analogs leading to positive therapeutic effects can be both receptor systems (mainly due to allosteric binding sites) and a directed change in the transcriptome due to changes in the activity of certain genes. All this opens up new perspectives for the creation of drugs with unique previously unknown characteristics. The introduction into medical practice of drugs capable of regulating the functional activity of the genome (in particular, the synthesis of trophic factors) gives a real opportunity to turn on the mechanisms of regeneration in humans in ontogenetically non-regenerating tissues (nervous system, heart, skeletal muscles, kidneys, etc.).