The devastating Varroa mite (Varroa destructor Anderson and Trueman) is an obligatory ectoparasite of the honey bee, contributing to significant colony losses in North America and throughout the world. The limited number of conventional acaricides to reduce Varroa mites and prevent disease in honey bee colonies is challenged with wide-spread resistance and low target-site selectivity. Here, we propose a biorational approach using comparative genomics for the development of honey bee-safe and selective acaricides targeting the Varroa mite-specific neuropeptidergic system regulated by proctolin, which is lacking in the honey bee. Proctolin is a highly conserved pentapeptide RYLPT (Arg-Tyr-Leu-Pro-Thr) known to act through a G protein-coupled receptor to elicit myotropic activity in arthropod species. A total of 33 different peptidomimetic and peptide variants were tested on the Varroa mite proctolin receptor. Ligand docking model and mutagenesis studies revealed the importance of the core aromatic residue Tyr2 in the proctolin ligand. Peptidomimetics were observed to have significant oral toxicity leading to the paralysis and death of Varroa mites, while there were no negative effects observed for honey bees. We have demonstrated that a taxon-specific physiological target identified by advanced genomics information offers an opportunity to develop Varroa mite-selective acaricides, hence, expedited translational processes.

Insect CAPA neuropeptidesare considered to affect water and ion balance by mediating the physiological metabolism activities of the Malpighian tubules. In previous studies, the CAPA-PK analogue 1895 (2Abf-Suc-FGPRLamide) was reported to decrease aphid fitness when administered through microinjection or via topical application. However, a further statistically significant decrease in the fitness of aphids and an increased mortality could not be established with pairwise combinations of 1895 with other CAPA analogue. In this study, we assessed the topical application of new combinations of 1895 with five CAPA-PVK analogues on the fitness of aphids. We found that 1895 and CAPA-PVK analogue 2315 (ASG-[β3 L]-VAFPRVamide) was statistically the most effective combination to control the peach potato aphid Myzus persicae nymphs via topical application, leading to 72% mortality. Additionally, the combination (1895+2315) was evaluated against a selection of beneficial insects, that is, a pollinator (Bombus terrestris) and three natural enemies (Chrysoperla carnea, Nasonia vitripennis, and Adalia bipunctata). We found no significant influence on food intake, weight increase, and survival for the pollinator and the three representative natural enemies. These results could facilitate to further establish and generate CAPA analogues as alternatives to broad spectrum and less friendly insecticides.

The core of Cyclolinopeptide A (CLA, cyclo(LIILVPPFF)), responsible for its high immunosuppressive activity, contains a Pro-Pro-Phe-Phe sequence. A newly synthesized cyclic tetrapeptide, cyclo(Pro-Pro-β3-HoPhe-Phe) (denoted as 4B8M) bearing the active sequence of CLA, was recently shown to exhibit a wide array of anti-inflammatory properties in mouse models. In this investigation, we demonstrate that the peptide significantly inhibits the replication of human adenovirus C serotype 5 (HAdV-5) and Herpes simplex virus type-1 (HSV-1) in epithelial lung cell line A-549, applying Cidofovir and Acyclovir as reference drugs. Based on a previously established mechanism of its action, we propose that the peptide may inhibit virus replication by the induction of PGE2 acting via EP2/EP4 receptors in epithelial cells. In summary, we reveal a new, antiviral property of this anti-inflammatory peptide.

A facile solid-phase synthetic method for incorporating the imidazoline ring motif, a surrogate for a trans peptide bond, into bioactive peptides is reported. The example described is the synthesis of an imidazoline peptidomimetic analog of an insect pyrokinin neuropeptide via a cyclization reaction of an iminium salt generated from the preceding amino acid and 2,4-diaminopropanoic acid (Dap).

Peptides are fragments of proteins that carry out biological functions. They act as signaling entities via all domains of life and interfere with protein-protein interactions, which are indispensable in bio-processes. Short peptides include fundamental molecular information for a prelude to the symphony of life. They have aroused considerable interest due to their unique features and great promise in innovative bio-therapies. This work focusing on the current state-of-the-art short peptide-based therapeutical developments is the first global review written by researchers from all continents, as a celebration of 100 years of peptide therapeutics since the commencement of insulin therapy in the 1920s. Peptide "drugs" initially played only the role of hormone analogs to balance disorders. Nowadays, they achieve numerous biomedical tasks, can cross membranes, or reach intracellular targets. The role of peptides in bio-processes can hardly be mimicked by other chemical substances. The article is divided into independent sections, which are related to either the progress in short peptide-based theranostics or the problems posing challenge to bio-medicine. In particular, the SWOT analysis of short peptides, their relevance in therapies of diverse diseases, improvements in (bio)synthesis platforms, advanced nano-supramolecular technologies, aptamers, altered peptide ligands and in silico methodologies to overcome peptide limitations, modern smart bio-functional materials, vaccines, and drug/gene-targeted delivery systems are discussed.

The synthesis of new analogues of cyclolinopeptide A (CLA) and their linear precursors modified with (R)- and (S)-4-methylpseudoproline in the Pro3-Pro4 fragment are presented. The peptides were tested in comparison with cyclosporine A (CsA) in concanavalin A (Con A) and pokeweed mitogen (PWM)-induced mouse splenocyte proliferation and in secondary humoral immune response in vitro to sheep erythrocytes (SRBC). Their effects on expression of selected signaling molecules in the Jurkat T cell line were also determined. In addition, the structural features of the peptides, applying nuclear magnetic resonance and circular dichroism, were analyzed. The results showed that only peptides 7 and 8 modified with (R)-4-methylpseudoproline residue (c(Leu1-Val2-(R)-(αMe)Ser(ΨPro)3-Pro4-Phe5-Phe6-Leu7-Ile8-Ile9) and c(Leu1-Val2-Pro3-(R)-(αMe)Ser(ΨPro)4-Phe5-Phe6-Leu7-Ile8-Ile9), respectively) strongly suppressed mitogen-induced splenocyte proliferation and the humoral immune response, with peptide 8 being more potent. Likewise, peptide 8 more strongly elevated expression of Fas, a proapoptotic signaling molecule in Jurkat cells. We postulate that the increased biological activity of peptide 8, compared to the parent molecule and other studied peptides, resulted from its more flexible structure, found on the basis of both CD and NMR studies. CD and NMR spectra showed that replacement of Pro3 by (R)-(αMe)Ser(¬Pro) caused much greater conformational changes than the same replacement of the Pro4 residue. Such a modification could lead to increased conformational freedom of peptide 8, resulting in a greater ability to adopt a more compact structure, better suited to its putative receptor. In conclusion, peptide 8 is a potent immune suppressor which may find application in controlling immune disorders.

A cyclic tetrapeptide Pro-Pro-Pheβ3ho-Phe (4B8M) was tested for immunosuppressive activity and potential therapeutic utility in several in vitro and in vivo mouse and human models. The tetrapeptide was less toxic for mouse splenocytes in comparison to cyclosporine A (CsA) and a parent cyclolinopeptide (CLA). The tetrapeptide demonstrated potent anti-inflammatory properties in antigen-specific skin inflammatory reactions to oxazolone and toluene diisocyanate as well to nonspecific irritants such as salicylic acid. It also inhibited inflammatory processes in an air pouch induced by carrageenan. In addition, 4B8M proved effective in amelioration of animal models corresponding to human diseases, such as nonspecific colon inflammation induced by dextran sulfate and allergic pleurisy induced by ovalbumin (OVA) in sensitized mice. The tetrapeptide lowered expression of EP1 and EP3 but not EP2 and EP4 prostaglandin E2 (PGE2) receptors on lipopolysaccharide-stimulated Jurkat T cells and ICAM-1 expression on human peripheral blood mononuclear cells (PBMC). Its anti-inflammatory property in the carrageenan reaction was blocked by EP3 and EP4 antagonists. In addition, 4B8M induced an intracellular level of PGE2 in a human KERTr keratinocyte cell line. In conclusion, 4B8M is a low toxic and effective inhibitor of inflammatory disorders with potential therapeutic use, affecting the metabolism of prostanoid family molecules.

The success of innovative drugs depends on an interdisciplinary and holistic approach to their design and development. The supramolecular architecture of living systems is controlled by non-covalent interactions to a very large extent. The latter are prone to extensive cooperation and like a virtuoso play a symphony of life. Thus, the design of effective ligands should be based on thorough knowledge on the interactions at either a molecular or high topological level. In this work, we emphasize the importance of supramolecular structure and ligand-based design keeping the potential of supramolecular H-bonding synthons in focus. In this respect, the relevance of supramolecular chemistry for advanced therapies is appreciated and undisputable. It has developed tools, such as Hirshfeld surface analysis, using a huge data on supramolecular interactions in over one million structures which are deposited in the Cambridge Structure Database (CSD). In particular, molecular interaction surfaces are useful for identification of macromolecular active sites followed by in silico docking experiments. Ornithine-derived compounds are a new, promising class of multi-targeting ligands for innovative therapeutics and cosmeceuticals. In this work, we present the synthesis together with the molecular and supramolecular structure of a novel ornithine derivative, namely N-α,N-δ)-dibenzoyl-(α)-hydroxymethylornithine, 1. It was investigated by modern experimental and in silico methods in detail. The incorporation of an aromatic system into the ornithine core induces stacking interactions, which are vital in biological processes. In particular, rare C=O…π intercontacts have been identified in 1. Supramolecular interactions were analyzed in all structures of ornithine derivatives deposited in the CSD. The influence of substituent was assessed by the Hirshfeld surface analysis. It revealed that the crystal packing is stabilized mainly by H…O, O…H, C…H, Cl (Br, F)…H and O…O interactions. Additionally, π…π, C-H…π and N-O…π interactions were also observed. All relevant H-bond energies were calculated using the Lippincott and Schroeder H-bond model. A library of synthons is provided. In addition, the large synthons (Long-Range Synthon Aufbau Module) were considered. The DFT optimization either in vacuo or in solutio yields very similar molecular species. The major difference with the relevant crystal structure was related to the conformation of terminal benzoyl C15-C20 ring. Furthermore, in silico prediction of the extensive physicochemical ADME profile (absorption, distribution, metabolism and excretion) related to the drug-likeness and medicinal chemistry friendliness revealed that a novel ornithine derivative 1 has the potential to be a new drug candidate. It has shown good in silico absorption and very low toxicity.

BACKGROUND:Kinins are multifunctional neuropeptides that regulate key insect physiological processes such as diuresis, feeding, and ecdysis. However, the physiological roles of kinins in ticks are unclear. Furthermore, ticks have an expanded number of kinin paracopies in the kinin gene. Silencing the kinin receptor (KR) in females of Rhipicephalus microplus reduces reproductive fitness. Thus, it appears the kinin signaling system is important for tick physiology and its disruption may have potential for tick control. RESULTS:We determined the activities of endogenous kinins on the KR, a G protein-coupled receptor, and identified potent peptidomimetics. Fourteen predicted R. microplus kinins (Rhimi-K), and 11 kinin analogs containing aminoisobutyric acid (Aib) were tested. The latter incorporated tick kinin sequences and/or were modified for enhanced resistance to arthropod peptidases. A high-throughput screen using a calcium fluorescence assay in 384-well plates was performed. All tested kinins and Aib analogs were full agonists. The most potent kinin and two kinin analogs were equipotent. Analogs 2414 ([Aib]FS[Aib]WGa) and 2412 ([Aib]FG[Aib]WGa) were the most active with EC50 values of 0.9 and 1.1 nM, respectively, matching the EC50 of the most potent tick kinin, Rhimi-K-14 (QDSFNPWGa) (EC50  = 1 nM). The potent analog 2415 ([Aib]FR[Aib]WGa, EC50  = 6.8 nM) includes both Aib molecules for resistance to peptidases and a positively charged residue, R, for enhanced water solubility and amphiphilic character. CONCLUSION:These tick kinins and pseudopeptides expand the repertoire of reagents for tick physiology and toxicology towards finding novel targets for tick management. © 2019 Society of Chemical Industry.

Neuropeptides belonging to the adipokinetic hormone (AKH) family elicit metabolic effects as their main function in insects, by mobilizing trehalose, diacylgycerol, or proline, which are released from the fat body into the hemolymph as energy sources for muscle contraction required for energy-intensive processes, such as locomotion. One of the AKHs produced in locusts is a decapeptide, Locmi-AKH-I (pELNFTPNWGT-NH2). A head-to-tail cyclic, octapeptide analog of Locmi-AKH-I, cycloAKH (cyclo[LNFTPNWG]) was synthesized to severely restrict the conformational freedom of the AKH structure. In vitro, cycloAKH selectively retains full efficacy on a pest insect (desert locust) AKH receptor, while showing little or no activation of the AKH receptor of a beneficial insect (honeybee). Molecular dynamic analysis incorporating NMR data indicate that cycloAKH preferentially adopts a type II β-turn under micelle conditions, whereas its linear counterpart and natural AKH adopts a type VI β-turn under similar conditions. CycloAKH, linear LNFTPNWG-NH2, and Locmi-AKH-I feature the same binding site during docking simulations with the desert locust AKH receptor (Schgr-AKHR), but differ in the details of the ligand/receptor interactions. However, cycloAKH failed to enter the binding pocket of the honeybee receptor 3D model during docking simulations. Since the locust AKH receptor has a greater tolerance than the honeybee receptor for the cyclic conformational constraint in vitro receptor assays, it could suggest a greater tolerance for a shift in the direction of the type II β turn exhibited by cycloAKH from the type VI β turn of the linear octapeptide and the native locust decapeptide AKH. Selectivity in biostable mimetic analogs could potentially be enhanced by incorporating conformational constraints that emphasize this shift. Biostable mimetic analogs of AKH offer the potential of selectively disrupting AKH-regulated processes, leading to novel, environmentally benign control strategies for pest insect populations.

Recently, fluorenylmethoxycarbonyl (Fmoc) amino acids (e.g. Fmoc-tyrosine or Fmoc-phenylalanine) have attracted growing interest in biomedical research and industry, with special emphasis directed towards the design and development of novel effective hydrogelators, biomaterials or therapeutics. With this in mind, a systematic knowledge of the structural and supramolecular features in recognition of those properties is essential. This work is the first comprehensive summary of noncovalent interactions combined with a library of supramolecular synthon patterns in all crystal structures of amino acids with the Fmoc moiety reported so far. Moreover, a new Fmoc-protected amino acid, namely, 2-{[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino}-3-{4-[(2-hydroxypropan-2-yl)oxy]phenyl}propanoic acid or N-fluorenylmethoxycarbonyl-O-tert-butyl-N-methyltyrosine, Fmoc-N-Me-Tyr(t-Bu)-OH, C29H31NO5, was successfully synthesized and the structure of its unsolvated form was determined by single-crystal X-ray diffraction. The structural, conformational and energy landscape was investigated in detail by combined experimental and in silico approaches, and further compared to N-Fmoc-phenylalanine [Draper et al. (2015). CrystEngComm, 42, 8047-8057]. Geometries were optimized by the density functional theory (DFT) method either in vacuo or in solutio. The polarizable conductor calculation model was exploited for the evaluation of the hydration effect. Hirshfeld surface analysis revealed that H...H, C...H/H...C and O...H/H...O interactions constitute the major contributions to the total Hirshfeld surface area in all the investigated systems. The molecular electrostatic potentials mapped over the surfaces identified the electrostatic complementarities in the crystal packing. The prediction of weak hydrogen-bonded patterns via Full Interaction Maps was computed. Supramolecular motifs formed via C-H...O, C-H...π, (fluorenyl)C-H...Cl(I), C-Br...π(fluorenyl) and C-I...π(fluorenyl) interactions are observed. Basic synthons, in combination with the Long-Range Synthon Aufbau Modules, further supported by energy-framework calculations, are discussed. Furthermore, the relevance of Fmoc-based supramolecular hydrogen-bonding patterns in biocomplexes are emphasized, for the first time.

Peptides, as drugs, evolution started with the penicillin discovery around a century ago (in 1928). There is no doubt that it changed the course of medicine. In recent years, peptide-based therapies have a significant renaissance of interest. The progress is visible in the number of peptide drugs approved [1]. Moreover, it has been extended in relation to cosmeceuticals only recently [2]. Notably, definition of cosmeceutical was introduced by Dr. Kligman for agents on the borderline of cosmetics and drugs, delivering a biological activity in support of cosmetic action [3]. Simple molecular building blocks (SMBBs), i.e. amino acids and oligopeptides (consisting of 2-20 amino acids), have gained an growing attention due to their numerous advantages (ease of large-scale synthesis, administration simplicity and superior properties: good stability, robustness, biocompatibility, natural availability, selective mode of action and low incidence of side effect, their easy modification for various purposes, i.e. chemical modification improves transdermal delivery of peptides, while cyclization enhances the affinity and selectivity) and applications (in anticancer therapy, immunology, drug delivery and so on) [4,5].

The title compound, N-benzoyl-2′-hydroxy-3-methylisovaline, representing synthon polymorphism, can be interesting inter alia from the point of view of modern supramolecular biofunctional materials. A novel crystalline phase (1) was successfully synthesized and its solid-state supramolecular architecture was comprehensively compared with the previously reported polymorphic form (2), deposited in the Cambridge Structural Database as Private Communication by Karr & Fronczek. Molecular conformation, qualitative and quantitative analysis of supramolecular interactions, including evaluation of their energies, were investigated by modern experimental and theoretical methods. The geometries of S and R enantiomers were optimized using DFT at the B3LYP-D3/6-311++G(d, p) basis set level of theory. The conformational structure of these stereoisomers in water was studied using the solvation CPCM model. Water has a slight effect on the geometry and relative stability of isomers. Hirhsfeld surface analysis revealed general similarity of interactions in both polymorphs and closely related isovaline derivatives retrieved from the Cambridge Structural Database, dominated by H⋯H, O⋯H/H⋯O and C⋯H/H⋯C intermolecular contacts, contributing to about 95% of the total HS area. Nevertheless, in (2) π … π stacking interactions play significant role in driving the polymorphism formation. The interplay of basic supramolecular synthons and long-range synthon aufbau modules at subsequent levels of the supramolecular architecture is discussed in detail. Overall, the supramolecular assemblies are composed of large synthons in the form of a layer in (1) and pseudohexagonally packed ribbons in (2), sustained by relatively strong H-bonds (alternating catemer-dimer mix) and π … π contacts, respectively. For a thorough and precise interpretation, two methodologies: Gavezzotti implemented in the PIXELC vs. a novel way via energy frameworks construction in the CrystalExplorer were used. It enabled deeper insight into the quantitative evaluation of the molecular pair-wise interactions energetics in the supramolecular structures of both polymorphs, revealing further differences between them.

Natalisins (NTLs) are conservative neuropeptides, which are only found in arthropods and are documented to regulate reproductive behaviors in insects. In our previous study, we have confirmed that NTLs regulate the reproductive process in an important agricultural pest, Bactrocera dorsalis (Hendel). Hence, in this study, to further confirm the in vivo function of NTL receptor (NTLR) and assess the potential of NTLR as an insecticide target, RNA interference targeting NTLR mRNA was performed. We found that mating frequencies of both males and females were reduced by RNAi-mediated knockdown of the NTLR transcript, while there was no effect on mating duration. Moreover, we functionally expressed the B. dorsalis NTLR in Chinese Hamster Ovary (CHO) cells and was co-transfected with an aequorin reporter to measure ligand activities. A total of 13 biostable multi-Aib analogs were tested for agonistic and antagonistic activities. While most of these NTL analogs did not show strong activity, one analog (NLFQV[Aib]DPFF[Aib]TRamide) had moderate antagonistic activity. Taken together, we provided evidence for the important roles of NTLR in regulating mating frequencies of both male and female in this fly and also provided in vitro data on mimetic analogs that serve as leading structures for the development of agonists and antagonists to disrupt the NTL signaling pathway.

Insect kinins modulate aspects of diuresis, digestion, development, and sugar taste perception in tarsi and labellar sensilla in mosquitoes. They are, however, subject to rapid biological degradation by endogenous invertebrate peptidases. A series of alpha-aminoisobutyric (Aib) acid-containing insect kinin analogs incorporating sequences native to the Aedes aegypti mosquito aedeskinins were evaluated on two recombinant kinin invertebrate receptors stably expressed in cell lines, discovering a number of highly potent and biostable insect kinin mimics. On the Ae. aegypti mosquito kinin receptor, three highly potent, biostable Aib analogs matched the activity of the Aib-containing biostable insect kinin analog 1728, which previously showed disruptive and/or aversive activity in aphid, mosquito and kissing bug. These three analogs are IK-Aib-19 ([Aib]FY[Aib]WGa, EC50 = 18 nM), IK-Aib-12 (pQKFY[Aib]WGa, EC50 = 23 nM) and IK-Aib-20 ([Aib]FH[Aib]WGa, EC50 = 28 nM). On the Rhipicephalus (Boophilus) microplus tick receptor, IK-Aib-20 ([Aib]FH[Aib]WGa, EC50 = 2 nM) is more potent than 1728 by a factor of 3. Seven other potentially biostable analogs exhibited an EC50 range of 5-10 nM, all of which match the potency of 1728. Among the multi-Aib hexapeptide kinin analogs tested the tick receptor has a preference for the positively-charged, aromatic H over the aromatic residues Y and F in the X-1 variable position ([Aib]FX1[Aib]WGa), whereas the mosquito receptor does not distinguish between them. In contrast, in a mono-Aib pentapeptide analog framework (FX1[Aib] WGa), both receptors exhibit a preference for Y over H in the variable position. Among analogs incorporating polyethylene glycol (PEG) polymer attachments at the Nterminus that can confer enhanced bioavailability and biostability, three matched or surpassed the potency of a positive control peptide. On the tick receptor IK-PEG-9 (P-8-R[Aib]FF[Aib]WGa) was the most potent. Two others, IK-PEG-8 (P-8-RFFPWGa) and IK-PEG-6 (P-4-RFFPWGa), were most potent on the mosquito receptor, with the first surpassing the activity of the positive control peptide. These analogs and others in the IK-Aib series expand the toolbox of potent analogs accessible to invertebrate endocrinologists studying the structural requirements for bioactivity and the as yet unknown role of the insect kinins in ticks. They may contribute to the development of selective, environmentally friendly pest arthropod control agents.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Cyclolinopeptide A (CLA), an immunosuppressive nonapeptide derived from linen seeds, was modified with S or R-γ4-bis(homo-phenylalanine) in positions 3 or 4, or both 3 and 4. These modifications changed the flexibility of new analogues and distribution of intramolecular hydrogen bonds. Analogues 11 c(Pro1-Pro2-Phe3-S-γ4-hhPhe4-Leu5-Ile6-Ile7-Leu8-Val9), 13 c(Pro1-Pro2-S-γ4-hhPhe3-R-γ4-hhPhe4-Leu5-Ile6-Ile7-Leu8-Val9) and 15 c(Pro1-Pro2-R-γ4-hhPhe3-Phe4-Leu5-Ile6-Ile7-Leu8-Val9) existed as a mixture of stable cis/trans isomers of Pro-Pro peptide bond. The comparison of the relative spatial orientations in crystal state of the two carbonyl groups, neighboring γ-amino acids, revealed conformational similarities to α-peptides. The addition of two -CH2- groups in γ-amino acids led to a more rigid conformation, although a more flexible one was expected. A significant difference in the relative orientation of the carbonyl groups was found for cyclic γ-peptides with a dominance of an antiparallel arrangement. As carbonyl groups may be engaged in the interactions with plausible receptors through hydrogen bonds, a similar biological activity of the modified peptides was expected. Our biological studies showed that certain cyclic, but not the corresponding linear peptides, lowered the viability of peripheral blood mononuclear cells (PBMC) at 100μg/mL concentration. The proliferation of PBMC induced by phytohemagglutinin A (PHA) was strongly inhibited by cyclic peptides only, in a dose-dependant manner. On the other hand, lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-α) production in whole blood cell cultures was inhibited by both linear and cyclic peptides. Peptide 15 c(Pro1-Pro2-R-γ4-hhPhe3-Phe4-Leu5-Ile6-Ile7-Leu8-Val9) blocked the expression of caspase-3, inhibited the expression of caspases-8 and -9 in 24h culture of Jurkat cells, and caused DNA fragmentation in these cells, as an indicator of apoptosis. Thus, we revealed a new mechanism of immunosuppressive action of a nonapeptide.