Synacton and individual activity of synthetic and natural corticotropins

Abstract

Short endogenous peptides represent one of the most important constituents of the mammalian body's general regulatory system. Some synthesized analogs and modified natural peptides (eg, corticotropins) also show high biological activity. Nevertheless, the mechanism of action of regulatory peptides remains unclear. To explain the effects of peptides of intermolecular processes, the hypothesis that a synactonal mechanism underlies the action of regulatory peptides, exemplified by the heptapeptide Semax, has been proposed. Thus, in the total pool of Semax metabolites, which includes the cleavage products of the parental molecule, we can distinguish the functional core, represented by the major metabolic products-peptides HFPGP and PGP. These peptides have their own binding sites with similar although differing characteristics. Together with Semax, they constitute a single complex of bioregulators acting in a certain sequence and in interaction, ie, synacton. It can be assumed that the diverse clinically significant effects of the drug Semax are determined by its synacton. Specific interactions between some tritium-labeled peptides (basic constituents of the Semax synacton) and plasma membranes of neurons have been characterized. Only a few peptides of the Semax synacton showed competitive activity for the Semax binding sites. Fragments comprising 5 amino acid residues (EHFPG and HFPGP) showed the highest competitive activity. We also characterized the processes of specific ligand-receptor interactions of some tritium-labeled corticotropins ([ H-Pro]MEHFPGP, [ H-Pro]HFPGP, and [ H-Pro]PGP) by applying mathematical discriminative models (Scatchard, Hill, Bjerrum, and Lineweaver-Burk plots). So the intermolecular interactions of these peptides with plasma membranes of neuronal brain targets are probably not limited by specific binding at orthosteric sites. The effect of peptides that act in the synacton considerably extends the regulatory potential of the initial molecule.

An integrated approach to study the molecular aspects of regulatory peptides biological mechanism

“…As it shown before, Semax and some derivative peptides (products of its biodegradation) have their own orthostatic sites of binding on different hypothetical selective receptors. The main characteristics of tritium‐labeled peptides' (Semax and the principal constituents of its synacton) specific binding to rat brain cells' plasmatic membranes (from various brain regions) are shown in Table .…”

“…The optimal conditions for “in vitro” experiments with peptides as well as the existence and characteristics of Semax and some of its derivative peptides specific binding in different rat brain regions (that is a second step of the proposed method) were determined earlier (see Section and Vyunova et al). Mathematical processing of these data has shown the possibility of existence of many molecular targets of Semax; some of them may represent the allosteric binding sites available on receptors of other neurotransmitters …”

“…In use of the mentioned above way, we found the existence and characterized specific binding places (located on brain cells plasmatic membranes) for a several groups of peptides, including Semax and some peptides—products of its biodegradation . Followed close mathematic analysis of Semax and derived peptides binding data let us to conclude that specific interactions of these peptides are complicated and not limited by the binding to their own orthosteric sites . We consider the possibility of peptide's allosteric binding sites or multiply cooperative binding sites, located on other types of neuroreceptors, existence.…”

Pharmacotranscriptomics of peptide drugs with neuroprotective properties

“…Thus, the same regulatory peptide can have its own highly specific binding sites on the cell surface, and can also affect the functioning of many sets of receptor groups related to different cell signaling systems 108 . Experimental data on the specific binding of peptides suggested the possibility of allosteric actions of peptides on various receptor systems, which leads to a change in the effect of endogenous orthosteric ligands and specific cell responses 1 . This explains the multifunctionality of peptides, as well as the specificity and subtle nature of their action.…”

“…To explain these actions of peptides on metabolic processes, the concept of a “synactone” mechanism has been proposed 1 . The essence of this concept is that, in addition to the peptide itself, it is possible to distinguish a functional core, represented by the main products of its metabolism.…”