Neuroscience & Medicine, 2013, 4, 223-252 223 Published Online December 2013 (http://www.scirp.org/journal/nm) http://dx.doi.org/10.4236/nm.2013.44035 A New Generation of Drugs: Synthetic Peptides Based on Natural Regulatory Peptides Timur Kolomin1*, Maria Shadrina1, Petr Slominsky1, Svetlana Limborska1, Nikolay Myasoedov2 1Department of Molecular Basis of Human Genetics, Institute of Molecular Genetics Russian Academy of Sciences, Moscow, Russia; 2Department of Chemistry of Physiologically Active Compounds, Institute of Molecular Genetics Russian Academy of Sciences, Moscow, Russia. Email: *[email protected] Received July 15th, 2013; revised August 13th, 2013; accepted September 10th, 2013 Copyright © 2013 Timur Kolomin et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. ABSTRACT Natural regulatory peptides are biologically active compounds that are produced by various cells and provide a link among the main regulatory systems of the body. The field of research into the biologic activity of endogenous regula- tory peptides is extremely vast. These peptides affect the cardiovascular, immune, reproductive, endocrine, digestive, and other systems, alter energy metabolism, and are especially effective in the regulation of the central nervous system. Despite of the wide range of preventive and therapeutic effects of natural regulatory peptides and proteins, their applica- tion in clinical practice is difficult. This is primarily because of their extreme instability, as they are rapidly degraded by proteases of the gastrointestinal tract, blood, cerebrospinal fluid, and other biologic media. Compounds with higher sta- bility (i.e., a considerably longer half-life compared with that of natural molecules) and the ability to provide a direc- tional effect on the various body systems were obtained from modifications of endogenous regulatory peptides. Syn- thetic analogs of regulatory peptides, as a rule, contain only natural amino acids in their composition, and their biodeg- radation does not lead to the formation of toxic products; thus, they have fewer side effects. This review focuses on the consideration of two synthetic regulatory peptides, Semax and Selank, which were the bases for the creation of new drugs that are used effectively in the treatment of various diseases of the nervous system. The synthetic analog of an adrenocorticotropic hormone 4 - 10 fragment (ACTH4-10) Semax is a powerful neuroprotective agent that is particularly effective as a therapy for stroke. Selank was synthesized on the basis of the natural immunomodulator tuftsin. Selank is a powerful anxiolytic that is used as a therapy for generalized anxiety disorder and neurasthenia without sedative and muscle-relaxant effects. This review presents the results of research aimed at studying the influence of these peptides on the transcriptome of brain cells. The problems of drugs developed based on the clinical activities of Semax and Selank are discussed separately. Keywords: Semax; Selank; Regulatory Peptides; ACTH; Tuftsin; Neuroprotection; Nootropes; Anxiolytics 1. Introduction type of research. Peptide substances have been shown to be the direct regulators or mediators of the majority of The development and investigation of novel neurotropic physiological processes that occur in the body. In addi- drugs seem to be a challenging scientific problem for tion, regulatory peptides exhibit a vast range of biologic modern biology and pharmacology. Effective and safe activities. pharmacological remedies that stimulate the cognitive Neuropeptides represent important regulators of the functions of the brain and are neuroprotective in different central nervous system. However, the study of the bio- pathologies of the central nervous system are needed logic properties and mechanisms of action of the major urgently. The use of endogenous regulators of the body, known neuropeptides revealed that the clinical applica- especially regulatory peptides, as a basis for the devel- tion of the full-size molecules of these compounds was opment of drugs that meet the requirements stated above extremely complicated because of their instability inside provides one of the most promising directions for this the body and the fugacity of their effects. In this context, *Corresponding author. it becomes necessary to use them as a basis of the de- Open Access NM 224 A New Generation of Drugs: Synthetic Peptides Based on Natural Regulatory Peptides velopment of more stable synthetic molecules by various life compared with that of their precursor proteins, which modifications, which might be more effective compared is a significant precondition for the rapid interruption of with their prototypes, and at the same time, less harmful the signal processes mediated by these molecules, in case for use in clinical settings. they become unnecessary [2]. The aim of this review is to consider the characteristics The mechanism of action of regulatory peptides in a of two new-generation peptide preparations: the synthetic target cell is conditioned by their binding to special analog of an adrenocorticotropic hormone 4 - 10 frag- membrane receptors. All regulatory peptides are plei- ment (ACTH4-10), the neuroprotector and nootrope Se- otropic and are able to influence a number of physio- max, and the natural immunopeptide tuftsin analog, the logical functions, with individual functions being simul- anxiolytic and nootrope Selank. Large-scale studies of taneously regulated by several peptides. The fact that the range of biologic activity and mechanism of action of regulatory peptides that affect target cells are able to Semax and Selank revealed that the therapeutic potential regulate the release of other regulatory peptides, which, of drugs derived from these compounds was far from in turn, initiate the generation of a new wave of regula- being exhausted, and that new indications for their ap- tory peptides, represents an important feature of their plication could be discovered. mechanism of action. This allowed Ashmarin et al. to Success in the creation of drugs based on the synthetic pinpoint the existence of cascade processes in the regu- peptides Semax and Selank and the achievement of posi- latory peptide system that sustain the effect of a single tive outcomes from their clinical applications required administration of a peptide for a considerable period (up the study of their mechanisms of action, as this opens to several days), whereas the half-life of the peptide does new approaches to the creation of pharmacologically not exceed several minutes. This sets forth the functional important molecules and reveals the impact of new tar- continuum of regulatory peptides that participate in the gets for the directed regulation of cellular functions in transfer of information among the systems of the body health and disease. (its organs, tissues, cell groups, and individual cells), thereby regulating their activity and integrating their 2. Natural and Synthetic Regulatory performance into a unity. Thus, the regulatory-peptide Peptides system is involved in the regulation of virtually all Regulatory peptides are universal endogenous biologic physiological responses of the body, and maintains the regulators of cellular functions in the body. They are part homeostasis of all of its systems [3-6]. of the most complicated system of specialized signaling All cells of the body permanently synthesize, and molecules, of which the principal function is the integra- support the required levels of, regulatory peptides. How- tion of the nervous, endocrine, and immune systems to ever, their biosynthesis undergoes changes in the pres- form a united functional continuum. ence of broken homeostasis. A similar instability occurs Extensive investigation of regulatory peptides began in during adaptive responses to the background of physical the 1970s after a team of Dutch researchers headed by or/and emotional strain, predisease conditions, etc., David de Wied demonstrated that the adrenocorticotropic thereby preventing the disturbance of the functional bal- hormone and its fragments affected the learning of ani- ance, which is an indication that the regulation of the mals [1]. Currently, over 9000 regulatory peptides that metabolism of endogenous peptides occurs at the cellular differ in both structure and properties have been de- level (transcription, translation, and posttranslation proc- scribed, the majority of which contain from 2 to 50 essing), at the tissue level (secretion and inactivation of amino acid residues and belong to the group of oligopep- regulatory peptides), and at the level of the body as a tides with no more than 20 amino acids or to the group of whole [7]. polypeptides with 20 to 100 amino acid residues. The classification of regulatory peptides takes into ac- Posttranslational processing is one of the main path- count their chemical and physiological structure and their ways of regulatory-peptide formation in the body, via origin. One of the main difficulties in classifying these which they are isolated from the physiologically inactive molecules lies in their multifunctional character, which precursor proteins with the help of specialized enzymes- does not allow one or even several functions to be estab- proteases. In some cases, a single precursor protein gives lished in a substrate. Considering the physiological and rise