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M. Quik - One of the best experts on this subject based on the ideXlab platform.
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Thymopoietin a thymic polypeptide prevents nicotinic agonist induced morphological changes in neonatal muscle cells in culture
Brain Research, 1992Co-Authors: M. Quik, J Philie, G GoldsteinAbstract:Abstract Thymopoietin, a polypeptide hormone isolated from thymus and involved in immune function, potently inhibited [125I]α-bungarotoxin binding to neonatal muscle cells in culture (IC50 = 3.8nM) and blocked carbachol-stimulated 22Na uptake with an IC50 of 1.9 ± 0.2nM and 23 ± 7nM at a half-maximal and maximal concentration of carbachol, respectively. Studies were subsequently done to evaluate potential long-term functional consequences of this interaction of Thymopoietin at the nicotinic receptor. Exposure (1–3 days) of neonatal muscle cells in culture to nicotine (3 × 10−6 M) or carbachol (1 × 10−6 M) resulted in a decline in myotube branching and a decrease in myotube length. Thymopoietin did not appreciably alter myotube morphology on its own; however, it prevented the effects of nicotine and carbachol on muscle cell morphology at concentrations (1–10 nM) which corresponded well to those with which Thymopoietin interacted at the receptor. The action of α-bungarotoxin on the myotubes was very similar to that of Thymopoietin. These studies suggest that the endogenously occurring polypeptide, Thymopoietin, has the potential to modulate muscle cell morphology through an interaction at the nicotinic receptor.
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Thymopoietin, a thymic polypeptide, potently interacts at muscle and neuronal nicotinic alpha-bungarotoxin receptors.
Molecular neurobiology, 1992Co-Authors: M. QuikAbstract:Current studies suggest that several distinct populations of nicotinic acetylcholine (ACh) receptors exist. One of these is the muscle-type nicotinic receptors with which neuromuscular nicotinic receptor ligands and the snake toxin alpha-bungarotoxin interact. alpha-Bungarotoxin potently binds to these nicotinic receptors and blocks their function, two characteristics that have made the alpha-toxin a very useful probe for the characterization of these sites. In neuronal tissues, several populations of nicotinic receptors have been identified which, although they share a nicotinic pharmacology, have unique characteristics. The alpha-bungarotoxin-insensitive neuronal nicotinic receptors, which may be involved in mediating neuronal excitability, bind nicotinic agonists with high affinity but do not interact with alpha-bungarotoxin. Subtypes of these alpha-toxin-insensitive receptors appear to exist, as evidenced by findings that some are inhibited by neuronal bungarotoxin whereas others are not. In addition to the alpha-bungarotoxin-insensitive sites, alpha-bungarotoxin-sensitive neuronal nicotinic receptors are also present in neuronal tissues. These latter receptors bind alpha-bungarotoxin with high affinity and nicotinic agonists with an affinity in the microM range. The function of the nicotinic alpha-bungarotoxin receptors are as yet uncertain. Thymopoietin, a polypeptide linked to immune function, appears to interact specifically with nicotinic receptor populations that bind alpha-bungarotoxin. Thus, in muscle tissue where alpha-bungarotoxin both binds to the receptor and blocks activity, Thymopoietin also potently binds to the receptor and inhibits nicotinic receptors-mediated function. In neuronal tissues, Thymopoietin interacts only with the nicotinic alpha-bungarotoxin site and not the alpha-bungarotoxin-insensitive neuronal nicotinic receptor population. These observations that Thymopoietin potently and specifically interacts with nicotinic alpha-bungarotoxin-sensitive receptors in neuronal and muscle tissue, together with findings that Thymopoietin is an endogenously occurring agent, could suggest that this immune-related polypeptide represents a ligand for the alpha-bungarotoxin receptors. The function of Thymopoietin at the alpha-bungarotoxin receptor is as yet uncertain; however, a potential trophic, as well as other roles are suggested.
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evidence for Thymopoietin and Thymopoietin alpha bungarotoxin nicotinic receptors within the brain
Proceedings of the National Academy of Sciences of the United States of America, 1991Co-Authors: M. Quik, U Babu, T Audhya, G GoldsteinAbstract:Thymopoietin, a polypeptide hormone of the thymus that has pleiotropic actions on the immune, endocrine, and nervous systems, potently interacts with the neuromuscular nicotinic acetylcholine receptor. Thymopoietin binds to the nicotinic alpha-bungarotoxin (alpha-BGT) receptor in muscle and, like alpha-BGT, inhibits cholinergic transmission at this site. Evidence is given that radiolabeled Thymopoietin similarly binds to a nicotinic alpha-BGT-binding site within the brain and does so with the characteristics of a specific receptor ligand. Thus specific binding to neuronal membranes was saturable, of high affinity (Kd = 8 nM), linear with increased tissue concentration, and readily reversible; half-time was approximately 5 min for association and 10 min for dissociation. Binding of 125I-labeled Thymopoietin was displaced not only by unlabeled Thymopoietin but also by alpha-BGT and the nicotinic receptor ligands d-tubocurarine and nicotine; various other receptor ligands (muscarinic, adrenergic, and dopaminergic) did not affect binding of 125I-labeled Thymopoietin. Thymopoietin was shown by ELISA to be present in brain extracts, displacement curves of thymus and brain extracts being parallel to the standard Thymopoietin curve, and Western (immuno) blot identified in brain and thymus extracts a Thymopoietin-immunoreactive polypeptide of the same molecular mass as purified Thymopoietin polypeptide. We conclude that Thymopoietin and Thymopoietin-binding sites are present within the brain and that the receptor for Thymopoietin is the previously identified nicotinic alpha-BGT-binding site of neuronal tissue.
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Thymopoietin a potent antagonist at nicotinic receptors in c2 muscle cell cultures
Molecular Pharmacology, 1991Co-Authors: M. Quik, Tapan Audhya, H Elbizri, Gideon GoldsteinAbstract:Recent work has shown that Thymopoietin, a polypeptide with actions in the immune and nervous systems, potently binds to the alpha-bungarotoxin (alpha-BGT) receptor. The present study was done to characterize the interaction of Thymopoietin at the nicotinic alpha-BGT binding site in cultured muscle cells and to correlate these findings with the effects of the polypeptide on nicotinic receptor-mediated function. Inhibition studies showed that Thymopoietin potently inhibited 125I-alpha-BGT binding in C2 muscle cells in culture, with an IC50 of 1.1 nM, a value similar to that for alpha-BGT. Thymopoietin bound to the alpha-BGT receptor in the cells in culture relatively slowly; at 10(-8) M Thymopoietin, maximal inhibition occurred after 45 to 75 min of exposure to the polypeptide. Dissociation of Thymopoietin from the receptor exhibited a much longer time course; recovery of alpha-BGT binding to control values after exposure to 10(-8) M Thymopoietin occurred approximately 16 hr after removal of the polypeptide. The effects of Thymopoietin on 125I-alpha-BGT binding correlated well with those on nicotinic function. Thymopoietin potently inhibited nicotinic receptor-mediated 22Na uptake in muscle cells in culture, with an IC50 of 2 nM. This effect was dependent on the length of the preincubation period with Thymopoietin, with maximal inhibition occurring after 60 min of exposure to the polypeptide. Recovery of the functional response after Thymopoietin (10(-8) M) exposure required about 16 hr. The mode of inhibition of receptor-mediated ion flux by Thymopoietin was similar to that observed with alpha-BGT but distinct from that obtained with d-tubocurarine and gallamine. To conclude, Thymopoietin, a thymic polypeptide associated with the immune system, potently inhibited both 125I-alpha-BGT binding and nicotinic receptor-mediated function in C2 muscle cells. These findings may have implications for myasthenia gravis and/or other neuromuscular disorders.
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Thymopoietin Potently and Specifically Interacts with the Nicotinic α-Bungarotoxin Receptor in Neuronal Tissue
Effects of Nicotine on Biological Systems, 1991Co-Authors: M. Quik, R. Afar, Gideon GoldsteinAbstract:Thymopoietin (TPO), a polypeptide linked to immune function, potently and specifically interacted at the α-bungarotoxin (BGT) receptor (IC50 = 3–10 nM) in neuronal membranes. As well, TPO up-regulated the α-BGT sites in neuronal cells in culture. In a neuronal cell line (PC12), TPO enhanced process formation suggesting that it may be a neurotrophic factor. Since TPO has been identified in nervous tissue, these findings suggest that the polypeptide may represent an endogenous ligand for the neuronal α-BGT site, possibly with a trophic role in neuronal function. Moreover, the present work provides further evidence for a link between the nervous and immune system.
Gideon Goldstein - One of the best experts on this subject based on the ideXlab platform.
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Brief Definitive Report TERMINAL DEOXYNUCLEOTIDYL TRANSFERASE IS FOUND IN PROTHYMOCYTES*
2013Co-Authors: E. Silverstone, Gideon Goldstein, Harvey Cantor, David BaltimoreAbstract:Terminal deoxynucleotidyl transferase is an enzyme which has the unique property of polymerizing polydeoxynucleotides onto a primer in the absence of a template (1, 2). This enzyme is found both in the thymus and the bone marrow of birds, rodents, and humans (3-7). Whether the marrow cells that contain terminal transferase are related to thymocytes, or are on a separate pathway of differentiation, is not yet known (7, 8). To determine the lineage of the murine bone marrow cells that have terminal transferase, we have investigated whether these cells have the antigen Thy-1 which is characteristic of T cells and thymocytes, or whether Thy-1 can be induced on the cells by treatment with Thymopoietin (9). Thymopoietin is known to induce a set of characteristic T-cell markers including the Thy-1 alloantigen on the surface of a subpopulation of bone marrow cells committed to T-cell differentiation (prothymocytes) (10). Destruction of Thy-l-positive cells after exposure to Thymopoietin allows elimination of a substantial fraction of those bone marrow cells that can repopulate an irradiated thymus (11). We find tha
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comparative efficacy of various routes of administration of thymopentin tp 5 with consideration of degradative mechanisms
International Journal of Peptide and Protein Research, 2009Co-Authors: Tapan Audhya, Gideon GoldsteinAbstract:Thymopoietin (originally termed TP-5 and now called thymopentin) is a synthetic pentapeptide that can reproduce the biological activity of the 49 amino acid thymic hormone Thymopoietin. The efficacy of various routes of administration of thymopentin was studied in mice and guinea pigs using an electromyographic assay as an end point to determine biological activity. In mice, the threshold dose necessary for a significant response when compared to controls was 0.03 mg/kg (mpk) for i.v. (intravenous) injection and 0.3 mpk for both i.p. (intraperitoneal) and s.c. (subcutaneous) injection. For the guinea pig, 0.03 mpk produced a significant response when compared to controls when injected either i.v. or s.c.; 0.3 mpk was required for a significant response for i.n. (intranasal) administration and 0.6 mpk for i.p. injection. When saline or plasma was injected, it produced no change in the electromyographic response. In plasma the pentapeptide is rapidly degraded by proteolytic enzymes. Treatment of plasma with specific enzyme inhibitors followed by incubation with thymopentin or Thymopoietin confirmed that serine protease and aminopeptidase M-like enzymes are responsible for the rapid inactivation of thymopentin in plasma, as measured by the electromyographic response.
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elevated plasma Thymopoietin associated with therapeutic nonresponsiveness in major depression
Biological Psychiatry, 2000Co-Authors: Gideon Goldstein, Maurizio Fava, Michael D Culler, Alan C Fisher, Karl Rickels, Bruce R Lydiard, Jerrold F RosenbaumAbstract:Abstract Background: Stress predisposes to major depression, and hyperactivity of the stress-activated hypothalamic-pituitary-adrenal (HPA) axis occurs in this disease. Thymopentin, an active fragment of Thymopoietin (TP), reduces endocrine and behavioral responses to experimental stress, possibly by lowering plasma TP (pTP) levels. Methods: Plasma TP and the HPA hormones arginine vasopressin (pAVP), adrenocorticotropic hormone (pACTH), and plasma cortisol (pCORT) were measured in 21 untreated depressed patients and 21 matched control subjects. Clinical responses to antidepressants were evaluated in 17 depressed patients. Results: Plasma TP was elevated in depression ( p p 7.5 pg/mL) versus 3 out of 10 (30%) with normal pTP ( p Conclusions: The significant association of elevated pTP with nonresponsiveness to antidepressant drugs may signify a distinct pathogenesis for the depression of patients with elevated pTP.
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iri 514 a synthetic peptide analogue of thymopentin reduces the behavioral response to social stress in rats
Physiology & Behavior, 1996Co-Authors: Frederique Menzaghi, Gideon Goldstein, Stephen C Heinrichs, Mauricio Vargascortes, George F KoobAbstract:Thymopentin, a synthetic pentapeptide (Arg-Lys-Asp-Val-Tyr) corresponding to amino acids 32-36 of the thymic polypeptide Thymopoietin, has been reported to block adrenocorticotrope responses to stress. The purpose of the present study was to explore potential antistress properties of a synthetic analogue of thymopentin, IRI-514 (Ac-Arg-Pro-Asp-Phe-NH2) using a behavioral response to a stressor. The behavioral response to social conflict stress (resident-intruder paradigm) was evaluated by the elevated plus-maze test of anxiety in adult Wistar rats. A single subcutaneous (SC) administration of IRI-514, 48 h before stress, dose-dependently reversed the anxiety-like behavior induced by the social stress. The effect of IRI-514 was present over an extended period (24-72 h) following SC administration and was maximally effective at a dose of 1 mg/kg. These results indicate that IRI-514 has a long-lasting modulatory effect on behavioral responses to a stressor, and suggest that Thymopoietin-derived peptides may have a role in modulating both behavioral and neuroendocrine responses to stress.
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Thymopoietin, a polypeptide ligand for the α-bungarotoxin binding site in brain: An autoradiographic study
Neuroscience, 1992Co-Authors: R. Afar, Paul B. S. Clarke, Gideon GoldsteinAbstract:Abstract Thymopoietin, a 48–49-amino acid polypeptide present in the thymus gland, was investigated as a potential ligand for the neuronal nicotinic α-bungarotoxin binding site in rat brain. Binding of [ 125 I]α-bungarotoxin to whole rat brain sections was inhibited by Thymopoietin in a concentration-dependent manner with an ic 50 of30.0 ± 8.2nM as compared to1.1 ± 0.3nM for α-bungarotoxin. However, at concentrations of Thymopoietin of up to 1 μM, [ 3 H]nicotine binding to high affinity sites was not inhibited. Thysplenin, a polypeptide with considerable homology to Thymopoietin did not affect [ 125 I]α-bungarotoxin binding. These results suggest that Thymopoietin selectively interacts with the nicotinic α-bungarotoxin binding site labelled by [ 125 I]α-bungarotoxin rather than the neuronal nicotinic receptor(s) labelled by [ 3 H]nicotine. Autoradiographic studies revealed that 1 μM Thymopoietin almost completely inhibited [ 125 I]α-bungarotoxin binding in all brain regions. Computer-assisted image analysis of displacement curves was performed on various brain areas rich in α-bungarotoxin binding, such as the dorsal endopiriform nucleus, fields 1 and 2 of Ammon's horn, the polymorph cell layer of the dentate gyrus and cortical layers 4 and 5. Thymopoietin inhibited [ 125 I]α-bungarotoxin binding with similar potency in all these regions, suggesting that it interacted at the same site in the different brain areas. The ic 50 values averaged over the six regions were24.6 ± 2.8nM for Thymopoietin and1.2 ± 0.2nM for α-bungarotoxin. These results show that Thymopoietin specifically interacted with the α-bungarotoxin site with a similar potency in different brain regions. It is suggested that Thymopoietin represents a selective ligand for α-bungarotoxin binding sites in brain.
G Goldstein - One of the best experts on this subject based on the ideXlab platform.
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Thymopoietin a thymic polypeptide prevents nicotinic agonist induced morphological changes in neonatal muscle cells in culture
Brain Research, 1992Co-Authors: M. Quik, J Philie, G GoldsteinAbstract:Abstract Thymopoietin, a polypeptide hormone isolated from thymus and involved in immune function, potently inhibited [125I]α-bungarotoxin binding to neonatal muscle cells in culture (IC50 = 3.8nM) and blocked carbachol-stimulated 22Na uptake with an IC50 of 1.9 ± 0.2nM and 23 ± 7nM at a half-maximal and maximal concentration of carbachol, respectively. Studies were subsequently done to evaluate potential long-term functional consequences of this interaction of Thymopoietin at the nicotinic receptor. Exposure (1–3 days) of neonatal muscle cells in culture to nicotine (3 × 10−6 M) or carbachol (1 × 10−6 M) resulted in a decline in myotube branching and a decrease in myotube length. Thymopoietin did not appreciably alter myotube morphology on its own; however, it prevented the effects of nicotine and carbachol on muscle cell morphology at concentrations (1–10 nM) which corresponded well to those with which Thymopoietin interacted at the receptor. The action of α-bungarotoxin on the myotubes was very similar to that of Thymopoietin. These studies suggest that the endogenously occurring polypeptide, Thymopoietin, has the potential to modulate muscle cell morphology through an interaction at the nicotinic receptor.
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evidence for Thymopoietin and Thymopoietin alpha bungarotoxin nicotinic receptors within the brain
Proceedings of the National Academy of Sciences of the United States of America, 1991Co-Authors: M. Quik, U Babu, T Audhya, G GoldsteinAbstract:Thymopoietin, a polypeptide hormone of the thymus that has pleiotropic actions on the immune, endocrine, and nervous systems, potently interacts with the neuromuscular nicotinic acetylcholine receptor. Thymopoietin binds to the nicotinic alpha-bungarotoxin (alpha-BGT) receptor in muscle and, like alpha-BGT, inhibits cholinergic transmission at this site. Evidence is given that radiolabeled Thymopoietin similarly binds to a nicotinic alpha-BGT-binding site within the brain and does so with the characteristics of a specific receptor ligand. Thus specific binding to neuronal membranes was saturable, of high affinity (Kd = 8 nM), linear with increased tissue concentration, and readily reversible; half-time was approximately 5 min for association and 10 min for dissociation. Binding of 125I-labeled Thymopoietin was displaced not only by unlabeled Thymopoietin but also by alpha-BGT and the nicotinic receptor ligands d-tubocurarine and nicotine; various other receptor ligands (muscarinic, adrenergic, and dopaminergic) did not affect binding of 125I-labeled Thymopoietin. Thymopoietin was shown by ELISA to be present in brain extracts, displacement curves of thymus and brain extracts being parallel to the standard Thymopoietin curve, and Western (immuno) blot identified in brain and thymus extracts a Thymopoietin-immunoreactive polypeptide of the same molecular mass as purified Thymopoietin polypeptide. We conclude that Thymopoietin and Thymopoietin-binding sites are present within the brain and that the receptor for Thymopoietin is the previously identified nicotinic alpha-BGT-binding site of neuronal tissue.
Wei Kong - One of the best experts on this subject based on the ideXlab platform.
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synthesis characterization and in vitro evaluation of a novel glycol chitosan edta conjugate to inhibit aminopeptidase mediated degradation of Thymopoietin oligopeptides
Molecules, 2017Co-Authors: Jiao Feng, Lili Cui, Nianqiu Shi, Yan Chen, Wei Kong, Yong ZhangAbstract:In this study, a novel conjugate consisting of glycol chitosan (GCS) and ethylene diamine tetraacetic acid (EDTA) was synthesized and characterized in terms of conjugation and heavy metal ion chelating capacity. Moreover, its potential application as a metalloenzyme inhibitor was evaluated with three Thymopoietin oligopeptides in the presence of leucine aminopeptidase. The results from FTIR and NMR spectra revealed that the covalent attachment of EDTA to GCS was achieved by the formation of amide bonds between the carboxylic acid group of EDTA and amino groups of GCS. The conjugated EDTA lost part of its chelating capacity to cobalt ions compared with free EDTA as evidenced by the results of cobalt ion chelation-mediated fluorescence recovery of calcein. However, further investigation confirmed that GCS-EDTA at low concentrations significantly inhibited leucine aminopeptidase-mediated degradation of all Thymopoietin oligopeptides.
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investigation into efficiency of a novel glycol chitosan bestatin conjugate to protect Thymopoietin oligopeptides from enzymatic degradation
Journal of Pharmaceutical Sciences, 2016Co-Authors: Yong Zhang, Jiao Feng, Lili Cui, Yuebin Zhang, Nianqiu Shi, Yan Chen, Wei KongAbstract:Abstract In this study, a novel glycol chitosan (GCS)–bestatin conjugate was synthesized and evaluated to demonstrate its efficacy in protecting Thymopoietin oligopeptides from aminopeptidase-mediated degradation. Moreover, the mechanism and relative susceptibility of three Thymopoietin oligopeptides, thymocartin (TP4), thymopentin (TP5), and thymotrinan (TP3), to enzymatic degradation were investigated and compared at the molecular level. Initial investigations indicated that formation of the GCS–bestatin conjugate, with a substitution degree of 7.0% (moles of bestatin per mole of glycol glucosamine unit), could significantly protect all 3 peptides from aminopeptidase-mediated degradation in a concentration-dependent manner. The space hindrance and loss of one pair of hydrogen bonds, resulting from the covalent conjugation of chitosan with bestatin, did not affect the specific interaction between bestatin and aminopeptidase. Moreover, TP4 displayed a higher degradation clearance compared with those of TP5 and TP3 under the same experimental conditions. The varying levels of susceptibility of these 3 peptides to aminopeptidase (TP4 > TP5 > TP3) were closely related to differences in their binding energies to enzyme, which mainly involved Van der Waals forces and electrostatic interactions, as supported by the results of molecular dynamics simulations. These results suggest that GCS–bestatin conjugate might be useful in the delivery of Thymopoietin oligopeptides by mucosal routes, and that TP3 and TP5 are better alternatives to TP4 for delivery because of their robust resistance against enzymatic degradation.
Yong Zhang - One of the best experts on this subject based on the ideXlab platform.
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synthesis characterization and in vitro evaluation of a novel glycol chitosan edta conjugate to inhibit aminopeptidase mediated degradation of Thymopoietin oligopeptides
Molecules, 2017Co-Authors: Jiao Feng, Lili Cui, Nianqiu Shi, Yan Chen, Wei Kong, Yong ZhangAbstract:In this study, a novel conjugate consisting of glycol chitosan (GCS) and ethylene diamine tetraacetic acid (EDTA) was synthesized and characterized in terms of conjugation and heavy metal ion chelating capacity. Moreover, its potential application as a metalloenzyme inhibitor was evaluated with three Thymopoietin oligopeptides in the presence of leucine aminopeptidase. The results from FTIR and NMR spectra revealed that the covalent attachment of EDTA to GCS was achieved by the formation of amide bonds between the carboxylic acid group of EDTA and amino groups of GCS. The conjugated EDTA lost part of its chelating capacity to cobalt ions compared with free EDTA as evidenced by the results of cobalt ion chelation-mediated fluorescence recovery of calcein. However, further investigation confirmed that GCS-EDTA at low concentrations significantly inhibited leucine aminopeptidase-mediated degradation of all Thymopoietin oligopeptides.
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investigation into efficiency of a novel glycol chitosan bestatin conjugate to protect Thymopoietin oligopeptides from enzymatic degradation
Journal of Pharmaceutical Sciences, 2016Co-Authors: Yong Zhang, Jiao Feng, Lili Cui, Yuebin Zhang, Nianqiu Shi, Yan Chen, Wei KongAbstract:Abstract In this study, a novel glycol chitosan (GCS)–bestatin conjugate was synthesized and evaluated to demonstrate its efficacy in protecting Thymopoietin oligopeptides from aminopeptidase-mediated degradation. Moreover, the mechanism and relative susceptibility of three Thymopoietin oligopeptides, thymocartin (TP4), thymopentin (TP5), and thymotrinan (TP3), to enzymatic degradation were investigated and compared at the molecular level. Initial investigations indicated that formation of the GCS–bestatin conjugate, with a substitution degree of 7.0% (moles of bestatin per mole of glycol glucosamine unit), could significantly protect all 3 peptides from aminopeptidase-mediated degradation in a concentration-dependent manner. The space hindrance and loss of one pair of hydrogen bonds, resulting from the covalent conjugation of chitosan with bestatin, did not affect the specific interaction between bestatin and aminopeptidase. Moreover, TP4 displayed a higher degradation clearance compared with those of TP5 and TP3 under the same experimental conditions. The varying levels of susceptibility of these 3 peptides to aminopeptidase (TP4 > TP5 > TP3) were closely related to differences in their binding energies to enzyme, which mainly involved Van der Waals forces and electrostatic interactions, as supported by the results of molecular dynamics simulations. These results suggest that GCS–bestatin conjugate might be useful in the delivery of Thymopoietin oligopeptides by mucosal routes, and that TP3 and TP5 are better alternatives to TP4 for delivery because of their robust resistance against enzymatic degradation.