Nowadays, there are more than 7 thousand diverse natural peptides have been described. Many of them, as well as their synthetic analogues, are of high interest from the point of view of medicine and pharma . Thus, at the beginning of 2020, the Food and Drug Administration (FDA) had approved more than 80 peptide drugs in the USA. The global market for peptide and protein drugs reached ~25.4 bln USD in 2018 . Russia also has its own original developments and a great history of peptide R&D. Back in 1933, Acad. V.P. Filatov had discovered bioactive extracts and hydrolysates from the tissues of organisms that included a significant content of peptides and were called “biogenic stimulants” at that time. This research field had got a powerful impetus after 1945 due to the demand of radioprotectors’ development. In 1947, A.V. Dorogov had obtained a mixed peptide drug ASD (rus. АСД). A number of original indigenous medicals had been developed in the USSR and the Russian Federation during 1946–2009, including Dalargin, Thymogen, Semax, Likopid, Immunofan, Thymodepressin, Deltaran, Gepon, Sedatin (veterinary drug), Bestim, Noopept, Stemokin (rus. Даларгин, Тимоген, Семакс, Ликопид, Иммунофан, Тимодепрессин, Дельтаран, Гепон, Седатин, Бестим, Ноопепт, Стемокин, respectively) and some others. Several successful outcomes deserve special attention. We have selected the most interesting and significant peptide substances that had carved out a niche in medical practice and in the pharmaceutical market, and the effectiveness of which had been confirmed by long-term experience of application. Hereinafter, we will take a closer look at four bright representatives of this set.
Semax (rus. Семакс, CAS 80714-61-0) belongs to the group of neuropeptides and is used as a nootropic drug. The peptide molecule includes seven amino acid residues: Met-Glu-His-Phe-Pro-Gly-Pro (MEHFPGP), that is reflected in the brand name – from abbr. “Seven amino acids”.
Semax was developed and obtained by Russian scientists under the supervision of Acad. I.P. Ashmarin (the Institute of Molecular Genetics, the Russian Academy of Sciences, formerly known as the Research Institute of Molecular Genetics of the Academy of Sciences of the Soviet Union) . Since 1982 the studies of this drug had being conducted for more than ten years. In the 1980s and 90s preclinical experiments have been performed many times in animals; in 1990–1994 – Phase I clinical trials and in 1994–1996 – phase II, and then the peptide was approved for medical practice . In the Russian Federation, Semax, which belongs to the pharmacotherapeutic group of nootropic drugs, according to the anatomical and therapeutic chemical classification – “other psychostimulants and nootropic drugs” (code N06BX), is registered as a medical drug (P N000812/01-150819) as 1% nasal drops and it is included into “The List of Vital and Essential Medicines” . Semax is used as part of complex therapy in the acute period of moderate to severe ischemic stroke . Semax is prescribed by practitioners for the treatment of hereditary degenerative diseases (Alzheimer’s and Parkinson’s disease, Huntington’s chorea) and chronic cerebrovascular insufficiency caused by cerebral vessels atherosclerosis .
Semax is characterized by a unique mechanism of neurospecific effect on the central nervous system. However, an exact description of the mechanism is still not given, but there are some known evidences that Semax acts on melanocortin receptors. It was reported that the peptide acts as an antagonist of α-melanocyte-stimulating hormone (α-MSH) toward melanocortin receptors MC4 и MC5 [8-10]. The drug affects an activation and expression of brain-derived neurotrophic factor (BDNF), which contributes to the development of neurons, and trkB, a receptor that enhances the neuronal viability .
Structurally, Semax is a synthetic analogue of corticotropin, which has antihypoxic, antioxidant, neuroprotective and psychostimulant action, but, at the same time, it does not demonstrate hormonal activity in contrast to closely related natural compounds . Practically, Semax does not show toxicity in various therapeutic schemes and it has a similar effect while being administered at a dose of ~ 6 thousand times less than piracetam (nootropil) . It should be noted that such terms as “nootropics” (greek nους – mind + τροπή – desire, affinity), “cognitive enhancers” or “smart drugs” are used to denote a variety of drugs that act on cognitive functions and are able to improve cognitive disorders .
The Semax peptide is a synthetic analogue of an adrenocorticotropic hormone fragment, namely – ACTH4-10. ACTH stimulates cognitive function in humans and rodents  and regulates production of glucocorticoids, which are hormones of the adrenal cortex – cortisone, cortisol, corticosterone; it modulates androgen, estrogen and progesterone levels . The bioavailability of Semax is high, especially via intranasal application. It penetrates the blood-brain barrier (BBB) in four minutes and the effects, such as cerebral circulation, attention and short-term memory improvement and hypoxic resistance, last about a 24-hour day after a single dose of 15–50 μg/kg [11, 15, 16]. This is due to the gradual peptide degradation, since half-life products retain biological activity. A significant part of the drug biological effects is retained by its degradation products. The most stable is Pro-Gly-Pro tripeptide, which is highly resistant to proteolysis . Thus, Semax can be considered as a stabilized ACTH4-7 peptide + Pro-Gly-Pro.
The studies of Semax bioactivity and of its potential novel applications are still ongoing. The drug became the basis for the development of its analogues. One of these drugs was Selank (rus. Селанк, CAS 129954-34-3), a nootropic peptide Thr-Lys-Pro-Arg-Pro-Gly-Pro, developed under the supervision of Acad. N. F. Myasoedov at the Institute of Molecular Genetics of the Russian Academy of Sciences . Selank is a synthetically modified short fragment of the immunoglobulin IgG heavy chain, elongated and stabilized, like Semax, by the insertion of Pro-Gly-Pro sequence. Besides, several Semax derivativesare at the early research stages, e.g., Acetyl Semax .
Dalargin (Tageflar, rus. Даларгин,CAS 81733-79-1) is a synthetic regulatory hexapeptide of the formula Tyr-D-Ala-Gly-Phe-Leu-Arg (YAGFLR), which is registered as a medicine in Russia (Р N001319/01-231209); pharmacotherapeutic group – peptic ulcer treatment. Dalargin is of interest, because it is an analog of two natural enkephalins that are methionine-enkephalin (Tyr-Gly-Gly-Phe-Met-COOH = YGGFM) and leucine-enkephalin (Tyr-Gly-Gly-Phe-Leu = YGGFL), in which the second glycine residue is replaced by D-alanine, and the C-terminus is replaced by arginine that is reflected in the brand name (Dalargin from D-Ala and Arg). Derivatization with help of D-amino acids is a well-known approach to increase a biological activity and resistance of peptide molecules against degradation in biological media . Replacing the C-termus with highly polar arginine was carried out to provide a peripheral action and hinder its penetration through BBB .
The therapeutic effect of Dalargin, an agonist of Δ-opioid receptors, is associated with its resemblance with enkephalins, which, in turn, are spatially similar to morphine. Thereby, these peptides reduce motor activity of the gastrointestinal tract and they are characterized by an analgesic action, which is observed only after direct administration into the brain due to their low proteolytic stability. The activity of peptides that are endogenous opiate receptor ligands can be fast and completely blocked by naloxone, an opiate antagonist, and this confirms the similarity of their properties to morphine . Endogenous ligands of morphine receptors had been identified in 1974 and this finding significantly stimulated the study of neuropeptides and their analogues. Dalargin had been obtained in the 1980s and initial trials were carried out in the Peptide Synthesis Laboratory of the All-Russian Scientific Center of Medical Sciences of the USSR under the supervision of Prof. M.I. Titov . Thus, the history of Dalargin lasts more than 35 years.
Dalargin promotes duodenal and stomach ulcer healing, inhibits necrosis foci progression, moderately reduces the secretion and acidity of gastric juice, as well as hyperenzymemia. The drug exhibits a weak hypotensive effect. Dalargin is prescribed for exacerbations of peptic ulcers, pancreatic necrosis and pancreatitis .
Besides that, immunological studies in laboratory animals demonstrated a modulating effect of opioid peptides on animal immune system ( B- and T-lymphocytes, phagocytic activity of lymphocytes, phagocytic index, bactericidal and lysozyme activity of blood serum), as a result of the opioid system activation via transcranial electrostimulation along with Dalargin administration . Since opioid peptides rapidly degrade under the influence of endopeptidases, researchers suggest that Dalargin acts as a trigger, initializing the body’s defense mechanisms. The obtained results confirm the assumption of immunomodulating properties of endo-opioid peptide analogues.
Dalargin causes a synergistic action in combination with certain peptides. It was found that intraperitoneal injections of Gly-His-Lys, dalargin, and thymogen (0.5, 1.2, and 0.5 μg/kg, respectively) resulted a concentration decrease of malondialdehyde in blood, as well as an increase of catalase activity and reparation, during a ten-day experiment in rats with bone fractures. The peptide composition was more potent than each single peptide being administered separately. Authors proposed this synergistic effect of peptides for stimulation of reparative osteogenesis . Dalargin was tested in rat wound healing model to accelerate damage reparation. Three days after injury, an increase in granulation was observed at dalargin concentrations of 10 μg/ml and 50 μg/ml (per os). Improvements were already observed at a concentration of 5 μg/ml. This confirms a stimulating effect on wound healing .
Recently, it was reported that Dalargin, due to its wound healing and immunostimulant properties, may be applied in therapy of the coronavirus disease (COVID-19), namely in treatment of severe pneumonia accompanied by respiratory failure . As a result of preliminary tests in an animal model of total alveolitis and interstitial pulmonary edema, it was shown that Dalargin had reduced cytokine release by 4 times (preventing a dangerous and potentially lethal response of the immune system, the so-called “cytokine storm syndrome”) and had significantly increased up to 70–100% survival rate of animals with acute respiratory distress syndrome versus 100% mortality in the control group after 72 hours. It was mentioned that various Dalargin administration schemes were applied, however, the experimental details are not disclosed.
Exploration of the amino acid content of various cytomedines (greek κύτος – cell + medium) of the pineal gland and thymus resulted a series of biologically active short peptides: Vilon (Lys-Glu), Thymogen and Epithalon . It emerged that, that such small synthetic molecules have even greater pharmacological activity at lower concentrations than their natural precursors, and they are characterized by tissue specificity, but do not show immunogenicity and species-specificity .
Thymogen (Oglufanide, Timogen, IM-862, rus. Тимоген, Оглюфанид, CAS 38101-59-6) is a short peptide consisting only of two amino acids: Glu-Trp (EW). This peptide is a drug registered in Russia in three different forms: as a solution for intramuscular injection with a concentration of 100 μg/ml (ЛС-002304-130911), as a dosed nasal spray containing 25 μg/dose (Р N002408/01-040210) and 0.05% topical cream (ЛСР-003508/07-210319) . Thymogen is a product of joint research by scientists from Moscow and Leningrad under the supervision of Corr. RAS V. Kh. Havinson; it had been obtained in the late 1980s, and since 1990 the peptide was introduced into medical practice [29, 30]. Thymogen is used as an immunomodulating agent in any pharmaceutical form for a wide range of purposes, which includes the prevention and treatment of viral and bacterial diseases of the upper respiratory tract, various infectious and inflammatory diseases, immunodeficiency, including side effects of chemo and radiotherapy, inhibition of regeneration and haematogenesis, etc. . The action of the drug is because its ability to modulate humoral and cellular immunity, to enhance the processes of regeneration and cellular metabolism of the body. In addition, Thymogen up-regulates the expression level of differentiating lymphocyte receptors, normalizes the concentration and ratio of T-lymphocytes (CD3+, CD4+ и CD8+), stimulates the production of immunoglobulins IgA, IgG, IgE and IgM.
As it was mentioned above, the mixture of Thymogen, Dalargin and the Gly-His-Lys enhances reparative osteogenesis . Thymogen, like other thymic peptides, exhibits a significant activating effect on the body reparation processes after radiation exposure and can increase survival in animal models, promoting the recovery of hematopoietic system and immunity .
Thymogen was investigated in the USA as a drug for treatment of different diseases related to the immune system, e.g., as an orphan drug for ovarian cancer therapy (NCT00003773, Phase I and NCT00017303, Phase II) . Trials of Thymogen as a co-drug for chemotherapy during the treatment of patients with metastatic colorectal cancer have also been conducted (NCT00006037, Phase III). The safety and effectiveness of the peptide in the treatment of Kaposi’s sarcoma in AIDS patients were studied (NCT00002445, Phase III). Unfortunately, the results of these experiments are unpublished. However, it is known that in Phase II clinical trials under metastatic renal cell cancer Thymogen has not demonstrated any effect on patients .
Note that there is a drug Bestim (rus. Бестим, Р N003335/03-030810), which is isomeric to Thymogen, consisting of the same amino acids, but in which, firstly, glutamine combines with tryptophan by the amide group in γ-position, and secondly, D-Glu is used . Bestim is also an immunostimulant that acts on humoral and cellular immunity, enhancing the body’s resistance toward bacteria and viruses. The pharmacological effect of the drug is close to that for Thymogen. Bestim is prescribed for secondary immunodeficiencies after injuries accompanied by purulent phenomena, in chronic septic conditions and various infectious diseases, such as tuberculosis, chlamydia, and viral hepatitis.
Thymodepressin is a drug closely related to Thymogen, that consists of γ-D-Glu-D-Trp . Here, as in the case of Bestim, glutamine is attached by the amide group, but tryptophan is represented by D-isomer, which leads to reversion of the drug properties. Thymodepressin, as reflected in its brand name, is an immunosuppressant registered for use in Russia (Р N000022/04-140308). This drug is prescribed for the treatment of many autoimmune diseases, including dermatoses, autoimmune pathologies of connective tissue, blood diseases, side effects of chemo and radiotherapy or transplantation.
Epithalon (Epitalon, AE-0 peptide, Эпиталон, CAS 307297-39-8) is a synthetic peptide with the amino acid sequence Ala-Glu-Asp-Gly (AEDG), developed on the basis of epithalamin preparation of natural origin, which is known as a powerful bioregulator of the neuroendocrine system [37, 38]. Epithalamin, an official peptide preparation of the pineal gland (epiphysis cerebri, conarium), and Epithalon, a tetrapeptide synthesized as a result of epithalamin sequence investigation, were obtained and studied at the St. Petersburg Institute of Bioregulation and Gerontology of the North-West RAMS under the supervision of Corr. RAS V.Kh. Havinson in 2002 . For the first time these peptide bioregulators had been identified in the 1970s by V. Kh. Havinson and V. G. Morozov in a pineal gland, in thymus and in the hypothalamic region of a brain . The pineal gland is an endocrine gland located in the brain of most vertebrates, where the production of the important hormone melatonin, which is a modulator of sleep and its structure in circadian and seasonal cycles, takes place . Melatonin has an antioxidant and immunostimulant effect . The increase of this endogenous neurotransmitter secretion under the influence of Epitalon is considered by researchers as one of effective strategies to stimulate immunity, especially in gerontological aspects.
Currently, Epithalon is still at the research step and it is not an official drug. However, the available experimental results indicate that this peptide is very promising from the point of view of future medical application. Epithalon is known to exhibit a wide range of biological effects. In particular, it is high-potential as a geroprotector, since it is able to elongate telomeres [43, 44], to reduce the symptoms of atherosclerosis, to inhibit the progression of aging and to increase the effectiveness of cognitive functions in all age cohorts . Moreover, this peptide has demonstrated an anticancer activity in animals [46, 47]. The peptide was able to stimulate the melatonin production by the pineal gland in in vivo trials in humans and primates [48, 49]. Compared to epithalamin, Epitalon was 50 times more effective than the natural product in terms of effecting on nighttime melatonin production , and also it proved to be a powerful normalizer of circadian dopamine and norepinephrine secretion rhythms in the hypothalamus .
Many researchers have noted that peptides, such as Epitalon, which can increase the melatonin concentration and do not cause adverse side effect, may be used in clinical geriatric therapy, since in elderly people with functional insufficiency of the pineal gland their psychomotor and physical performance is 20–40% lower than an age norm . The consequences of this dysfunction are circadian rhythm disturbances, changes in the melatonin blood concentration, autonomic regulation, body temperature and deterioration of the cardiovascular system, and thus accelerated aging of such patients occurs.
Thus, the development of new peptide drugs and the research for original applications of already known compounds, as well as their chemical modification, will help to expand the scope of peptide drugs. Peptides, due to their unique properties and affinity for natural endogenous compounds of the human body, demonstrate excellent potential as future medicines for solving many serious medical issues.
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