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Sugiura, Takumi, Takurou Kanada, Daisuke Mori, Hiroyuki Sakai, Aya Shibata, Yoshiaki Kitamura i Masato Ikeda. "Chemical stimulus-responsive supramolecular hydrogel formation and shrinkage of a hydrazone-containing short peptide derivative". Soft Matter 16, nr 4 (2020): 899–906. http://dx.doi.org/10.1039/c9sm01969c.
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Mei, Jingjing, Xiaoli Zhang, Meifeng Zhu, Jianing Wang, Ling Wang i Lianyong Wang. "Barium-triggered β-sheet formation and hydrogelation of a short peptide derivative". RSC Adv. 4, nr 3 (2014): 1193–96. http://dx.doi.org/10.1039/c3ra45023f.
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Belyaeva, Veronika S., Yulia V. Stepenko, Igor I. Lyubimov, Alexandr L. Kulikov, Alesia A. Tietze, Indira S. Kochkarova, Olga V. Martynova i in. "Non-hematopoietic erythropoietin-derived peptides for atheroprotection and treatment of cardiovascular diseases". Research Results in Pharmacology 6, nr 3 (30.09.2020): 75–86. http://dx.doi.org/10.3897/rrpharmacology.6.58891.
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Relevance: Cardiovascular diseases continue to be the leading cause of premature adult death. Lipid profile and atherogenesis: Dislipidaemia leads to subsequent lipid accumulation and migration of immunocompetent cells into the vessel intima. Macrophages accumulate cholesterol forming foam cells – the morphological substrate of atherosclerosis in its initial stage. Inflammation and atherogenesis: Pro-inflammatory factors provoke oxidative stress, vascular wall damage and foam cells formation. Endothelial and mitochondrial dysfunction in the development of atherosclerosis: Endothelial mitochondria are some of the organelles most sensitive to oxidative stress. Damaged mitochondria produce excess superoxide and H2O2, which are the main factors of intracellular damage, further increasing endothelial dysfunction. Short non-hematopoietic erythropoietin-based peptides as innovative atheroprotectors: Research in recent decades has shown that erythropoietin has a high cytoprotective activity, which is mainly associated with exposure to the mitochondrial link and has been confirmed in various experimental models. There is also a short-chain derivative, the 11-amino acid pyroglutamate helix B surface peptide (PHBSP), which selectively binds to the erythropoietin heterodymic receptor and reproduces its cytoprotective properties. This indicates the promising use of short-chain derivatives of erythropoietin for the treatment and prevention of atherosclerotic vascular injury. In the future, it is planned to study the PHBSP derivatives, the modification of which consists in adding RGD and PGP tripeptides with antiaggregant properties to the original 11-member peptide.
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Radzishevsky, Inna S., Shahar Rotem, Fadia Zaknoon, Leonid Gaidukov, Arie Dagan i Amram Mor. "Effects of Acyl versus Aminoacyl Conjugation on the Properties of Antimicrobial Peptides". Antimicrobial Agents and Chemotherapy 49, nr 6 (czerwiec 2005): 2412–20. http://dx.doi.org/10.1128/aac.49.6.2412-2420.2005.
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ABSTRACT To investigate the importance of increased hydrophobicity at the amino end of antimicrobial peptides, a dermaseptin derivative was used as a template for a systematic acylation study. Through a gradual increase of the acyl moiety chain length, hydrophobicity was monitored and further modulated by acyl conversion to aminoacyl. The chain lengths of the acyl derivatives correlated with a gradual increase in the peptide's global hydrophobicity and stabilization of its helical structure. The effect on cytolytic properties, however, fluctuated for different cells. Whereas acylation gradually enhanced hemolysis of human red blood cells and antiprotozoan activity against Leishmania major, bacteria displayed a more complex behavior. The gram-positive organism Staphylococcus aureus was most sensitive to intermediate acyl chains, while longer acyls gradually led to a total loss of activity. All acyl derivatives were detrimental to activity against Escherichia coli, namely, but not solely, because of peptide aggregation. Although aminoacyl derivatives behaved essentially similarly to the nonaminated acyls, they displayed reduced hydrophobicity, and consequently, the long-chain acyls enhanced activity against all microorganisms (e.g., by up to 12-fold for the aminolauryl derivative) but were significantly less hemolytic than their acyl counterparts. Acylation also enhanced bactericidal kinetics and peptide resistance to plasma proteases. The similarities and differences upon acylation of MSI-78 and LL37 are presented and discussed. Overall, the data suggest an approach that can be used to enhance the potencies of acylated short antimicrobial peptides by preventing hydrophobic interactions that lead to self-assembly in solution and, thus, to inefficacy against cell wall-containing target cells.
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Giannecchini, Simone, Armida Di Fenza, Anna Maria D'Ursi, Donatella Matteucci, Paolo Rovero i Mauro Bendinelli. "Antiviral Activity and Conformational Features of an Octapeptide Derived from the Membrane-Proximal Ectodomain of the Feline Immunodeficiency Virus Transmembrane Glycoprotein". Journal of Virology 77, nr 6 (15.03.2003): 3724–33. http://dx.doi.org/10.1128/jvi.77.6.3724-3733.2003.
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ABSTRACT Feline immunodeficiency virus (FIV) provides a valuable animal model by which criteria for lentivirus control strategies can be tested. Previous studies have shown that a 20-mer synthetic peptide of the membrane-proximal ectodomain of FIV transmembrane glycoprotein, designated peptide 59, potently inhibited the growth of tissue culture-adapted FIV in feline fibroblastoid CrFK cells. In the present report we describe the potential of this peptide to inhibit the replication of primary FIV isolates in lymphoid cells. Because antiviral activity of peptide 59 was found to map to a short segment containing three conserved Trp residues, further analyses focused on a derivative of eight amino acids (770W-I777), designated C8. Peptide C8 activity was found to be dependent on conservation of the Trp motif, to be removed from solution by FIV absorbed onto substrate cells, and to be blocked by a peptide derived from the N-terminal portion of FIV transmembrane glycoprotein. Structural studies showed that peptide C8 possesses a conformational propensity highly uncommon for peptides of its size, which may account for its considerable antiviral potency in spite of small size.
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Bai, Fengwei, Terrence Town, Deepti Pradhan, Jonathan Cox, Ashish, Michel Ledizet, John F. Anderson i in. "Antiviral Peptides Targeting the West Nile Virus Envelope Protein". Journal of Virology 81, nr 4 (6.12.2006): 2047–55. http://dx.doi.org/10.1128/jvi.01840-06.
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ABSTRACT West Nile virus (WNV) can cause fatal murine and human encephalitis. The viral envelope protein interacts with host cells. A murine brain cDNA phage display library was therefore probed with WNV envelope protein, resulting in the identification of several adherent peptides. Of these, peptide 1 prevented WNV infection in vitro with a 50% inhibition concentration of 67 μM and also inhibited infection of a related flavivirus, dengue virus. Peptide 9, a derivative of peptide 1, was a particularly potent inhibitor of WNV in vitro, with a 50% inhibition concentration of 2.6 μM. Moreover, mice challenged with WNV that had been incubated with peptide 9 had reduced viremia and fatality compared with control animals. Peptide 9 penetrated the murine blood-brain barrier and was found in the brain parenchyma, implying that it may have antiviral activity in the central nervous system. These short peptides serve as the basis for developing new therapeutics for West Nile encephalitis and, potentially, other flaviviruses.
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Falla, T. J., i R. E. Hancock. "Improved activity of a synthetic indolicidin analog." Antimicrobial Agents and Chemotherapy 41, nr 4 (kwiecień 1997): 771–75. http://dx.doi.org/10.1128/aac.41.4.771.
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A novel cationic peptide, CP-11, based on the structure of the bovine neutrophil peptide indolicidin, was designed to increase the number of positively charged residues, maintain the short length (13 amino acids), and enhance the amphipathicity relative to those of indolicidin. CP-11, and especially its carboxymethylated derivative, CP-11C, demonstrated improved activity against gram-negative bacteria and Candida albicans, while it maintained the activity of indolicidin against staphylococci and demonstrated a reduced ability to lyse erythrocytes. In Escherichia coli, CP-11 was better able than indolicidin to permeabilize both the outer membrane, as indicated by the enhancement of uptake of 1-N-phenylnaphthylamine, and the inner membrane, as determined by the unmasking of cytoplasmic beta-galactosidase, providing an explanation for its improved activity.
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Praveen, Praveen, Chao Wang, Thomas N. G. Handley, Hongkang Wu, Chrishan S. Samuel, Ross A. D. Bathgate i Mohammed Akhter Hossain. "A Lipidated Single-B-Chain Derivative of Relaxin Exhibits Improved In Vitro Serum Stability without Altering Activity". International Journal of Molecular Sciences 24, nr 7 (1.04.2023): 6616. http://dx.doi.org/10.3390/ijms24076616.
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Human relaxin-2 (H2 relaxin) is therapeutically very important due to its strong anti-fibrotic, vasodilatory, and cardioprotective effects. Therefore, relaxin’s receptor, relaxin family peptide receptor 1 (RXFP1), is a potential target for the treatment of fibrosis and related disorders, including heart failure. H2 relaxin has a complex two-chain structure (A and B) and three disulfide bridges. Our laboratory has recently developed B7-33 peptide, a single-chain agonist based on the B-chain of H2 relaxin. However, the peptide B7-33 has a short circulation time in vitro in serum (t1/2 = ~6 min). In this study, we report structure-activity relationship studies on B7-33 utilizing different fatty-acid conjugations at different positions. We have shown that by fatty-acid conjugation with an appropriate spacer length, the in vitro half-life of B7-33 can be increased from 6 min to 60 min. In the future, the lead lipidated molecule will be studied in animal models to measure its PK/PD properties, which will lead to their pre-clinical applications.
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Rosa, Elisabetta, Enrico Gallo, Teresa Sibillano, Cinzia Giannini, Serena Rizzuti, Eliana Gianolio, Pasqualina Liana Scognamiglio, Giancarlo Morelli, Antonella Accardo i Carlo Diaferia. "Incorporation of PEG Diacrylates (PEGDA) Generates Hybrid Fmoc-FF Hydrogel Matrices". Gels 8, nr 12 (16.12.2022): 831. http://dx.doi.org/10.3390/gels8120831.
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Generated by a hierarchical and multiscale self-assembling phenomenon, peptide-based hydrogels (HGs) are soft materials useful for a variety of applications. Short and ultra-short peptides are intriguing building blocks for hydrogel fabrication. These matrices can also be obtained by mixing low-molecular-weight peptides with other chemical entities (e.g., polymers, other peptides). The combination of two or more constituents opens the door to the development of hybrid systems with tunable mechanical properties and unexpected biofunctionalities or morphologies. For this scope, the formulation, the multiscale analysis, and the supramolecular characterization of novel hybrid peptide-polymer hydrogels are herein described. The proposed matrices contain the Fmoc-FF (Nα-fluorenylmethyloxycarbonyl diphenylalanine) hydrogelator at a concentration of 0.5 wt% (5.0 mg/mL) and a diacrylate α-/ω-substituted polyethylene-glycol derivative (PEGDA). Two PEGDA derivatives, PEGDA 1 and PEGDA2 (mean molecular weights of 575 and 250 Da, respectively), are mixed with Fmoc-FF at different ratios (Fmoc-FF/PEGDA at 1/1, 1/2, 1/5, 1/10 mol/mol). All the multicomponent hybrid peptide-polymer hydrogels are scrutinized with a large panel of analytical techniques (including proton relaxometry, FTIR, WAXS, rheometry, and scanning electronic microscopy). The matrices were found to be able to generate mechanical responses in the 2–8 kPa range, producing a panel of tunable materials with the same chemical composition. The release of a model drug (Naphthol Yellow S) is reported too. The tunable features, the different topologies, and the versatility of the proposed materials open the door to the development of tools for different applicative areas, including diagnostics, liquid biopsies and responsive materials. The incorporation of a diacrylate function also suggests the possible development of interpenetrating networks upon cross-linking reactions. All the collected data allow a mutual comparison between the different matrices, thus confirming the significance of the hybrid peptide/polymer-based methodology as a strategy for the design of innovative materials.
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Barreto-Santamaría, Adriana, Zuly Jenny Rivera, Javier Eduardo García, Hernando Curtidor, Manuel Elkin Patarroyo, Manuel Alfonso Patarroyo i Gabriela Arévalo-Pinzón. "Shorter Antibacterial Peptide Having High Selectivity for E. coli Membranes and Low Potential for Inducing Resistance". Microorganisms 8, nr 6 (8.06.2020): 867. http://dx.doi.org/10.3390/microorganisms8060867.
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Antimicrobial peptides (AMPs) have been recognised as a significant therapeutic option for mitigating resistant microbial infections. It has been found recently that Plasmodium falciparum-derived, 20 residue long, peptide 35409 had antibacterial and haemolytic activity, making it an AMP having reduced selectivity, and suggesting that it should be studied more extensively for obtaining new AMPs having activity solely targeting the bacterial membrane. Peptide 35409 was thus used as template for producing short synthetic peptides (<20 residues long) and evaluating their biological activity and relevant physicochemical characteristics for therapeutic use. Four of the sixteen short peptides evaluated here had activity against E. coli without any associated haemolytic effects. The 35409-1 derivative (17 residues long) had the best therapeutic characteristics as it had high selectivity for bacterial cells, stability in the presence of human sera, activity against E. coli multiresistant clinical isolates and was shorter than the original sequence. It had a powerful membranolytic effect and low potential for inducing resistance in bacteria. This peptide’s characteristics highlighted its potential as an alternative for combating infection caused by E. coli multiresistant bacteria and/or for designing new AMPs.
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Lyons, R. H., B. Q. Ferguson i M. Rosenberg. "Pentapeptide nuclear localization signal in adenovirus E1a". Molecular and Cellular Biology 7, nr 7 (lipiec 1987): 2451–56. http://dx.doi.org/10.1128/mcb.7.7.2451-2456.1987.
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The adenovirus E1a gene products are nuclear proteins important in transcriptional control of viral functions during infection. By producing normal E1a proteins and derivatives of E1a in bacteria and microinjecting these proteins into cultured cells, we were able to examine their ability to localize to the nucleus. We showed that a short peptide sequence at the carboxyl terminus of E1a is necessary for the rapid (30-min) nuclear localization of that protein. Additionally, we showed that just the last five amino acids of E1a are sufficient to direct nuclear accumulation of a heterologous protein, Escherichia coli galactokinase, with the same kinetics as native E1a. The mechanism by which this pentamer mediates rapid nuclear localization was examined by testing the ability of a galactokinase derivative which has no signal pentamer to exit the nucleus, as well as to enter it. Because neither free entry nor exit was detected, the effect of the signal is unlikely to be through increased nuclear retention of freely diffusible proteins but rather by enhancement of entry into the nucleus.
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Lyons, R. H., B. Q. Ferguson i M. Rosenberg. "Pentapeptide nuclear localization signal in adenovirus E1a." Molecular and Cellular Biology 7, nr 7 (lipiec 1987): 2451–56. http://dx.doi.org/10.1128/mcb.7.7.2451.
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The adenovirus E1a gene products are nuclear proteins important in transcriptional control of viral functions during infection. By producing normal E1a proteins and derivatives of E1a in bacteria and microinjecting these proteins into cultured cells, we were able to examine their ability to localize to the nucleus. We showed that a short peptide sequence at the carboxyl terminus of E1a is necessary for the rapid (30-min) nuclear localization of that protein. Additionally, we showed that just the last five amino acids of E1a are sufficient to direct nuclear accumulation of a heterologous protein, Escherichia coli galactokinase, with the same kinetics as native E1a. The mechanism by which this pentamer mediates rapid nuclear localization was examined by testing the ability of a galactokinase derivative which has no signal pentamer to exit the nucleus, as well as to enter it. Because neither free entry nor exit was detected, the effect of the signal is unlikely to be through increased nuclear retention of freely diffusible proteins but rather by enhancement of entry into the nucleus.
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Navalkissoor, Shaunak, i Ashley Grossman. "Targeted Alpha Particle Therapy for Neuroendocrine Tumours: The Next Generation of Peptide Receptor Radionuclide Therapy". Neuroendocrinology 108, nr 3 (23.10.2018): 256–64. http://dx.doi.org/10.1159/000494760.
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Neuroendocrine tumours (NETs) are being seen increasingly frequently, but to date only complete surgical resection is curative. However, among the various therapeutic options, peptide receptor radionuclide therapy, linking a radioactive moiety to an octreotide derivative, has been shown to be highly efficacious and a well-tolerated therapy, improving progression-free survival and probably overall survival. Nevertheless, the current radionuclides in use are beta particle emitters with non-optimal radiobiological properties. A new generation of alpha particle-emitting radionuclides is being developed, with advantages in terms of very high energy and a short path length, which should theoretically show higher efficacy. We survey the current developments in this field, emphasising the exciting potential of this novel form of therapy for NETs.
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Evans, AA, S. Khan i ME Smith. "Evidence for a hormonal action of beta-endorphin to increase glucose uptake in resting and contracting skeletal muscle". Journal of Endocrinology 155, nr 2 (1.11.1997): 387–92. http://dx.doi.org/10.1677/joe.0.1550387.
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The uptake of 2-[3H]deoxyglucose, a non-metabolisable derivative of glucose, was studied in resting and contracting muscle. An isolated phrenic nerve/hemidiaphragm preparation of the mouse was used, and contractions of the muscle were elicited by electrical stimulation of the nerve. beta-Endorphin stimulated the uptake of 2-deoxyglucose in resting diaphragm muscle. The rate of uptake in the presence of the optimum concentration of beta-endorphin was similar to that in the presence of the optimum concentration of insulin over the short incubation period. beta-Endorphin also stimulated the uptake of 2-deoxyglucose in contracting muscle, but the optimum concentration of the peptide for this effect was three orders of magnitude lower than in resting muscle. The optimum concentration for insulin, however, was similar in resting and contracting muscle. An analogue of the C-terminal tetrapeptide of beta-endorphin also stimulated 2-deoxyglucose uptake, but this peptide was equally efficacious in resting and contracting muscle. It is suggested that beta-endorphin, which is released into the circulation during exercise, may have a hormonal action to increase the uptake of glucose during muscular activity. This peptide or its metabolites may be partly responsible for the insulin-independent uptake of glucose during exercise.
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Santamaría, Carlos, Silda Larios, Steve Quirós, Javier Pizarro-Cerda, Jean-Pierre Gorvel, Bruno Lomonte i Edgardo Moreno. "Bactericidal and Antiendotoxic Properties of Short Cationic Peptides Derived from a Snake Venom Lys49 Phospholipase A2". Antimicrobial Agents and Chemotherapy 49, nr 4 (kwiecień 2005): 1340–45. http://dx.doi.org/10.1128/aac.49.4.1340-1345.2005.
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ABSTRACT The activities of short synthetic, nonhemolytic peptides derived from the C-terminal region of myotoxin II, a catalytically inactive phospholipase A2 homologue present in the venom of the snake Bothrops asper, have been shown to reproduce the bactericidal activity of the parent protein. They combine cationic and hydrophobic-aromatic amino acids, thus functionally resembling the antimicrobial peptides of innate defenses. This study evaluated the antimicrobial and antiendotoxic properties of a 13-mer derivative peptide of the C-terminal sequence from positions 115 to 129 of myotoxin II, named pEM-2. This peptide (KKWRWWLKALAKK) showed bactericidal activity against both gram-positive and gram-negative bacteria. In comparison to previously described peptide variants derived from myotoxin II, the toxicity of pEM-2 toward eukaryotic cells in culture was significantly reduced, being similar to that of lactoferricin B but lower than that of polymyxin B. The all-d enantiomer of pEM-2 [pEM-2 (d)] retained the same bactericidal potency of its l-enantiomeric counterpart, but it showed an enhanced ability to counteract the lethal activity of an intraperitoneal lipopolysaccharide challenge in mice, which correlated with a significant reduction of the serum tumor necrosis factor alpha levels triggered by this endotoxin. Lethality induced by intraperitoneal infection of mice with Escherichia coli or Salmonella enterica serovar Typhimurium was reduced by the administration of pEM-2 (d). These results demonstrate that phospholipase A2-derived peptides may have the potential to counteract microbial infections and encourage further evaluations of their actions in vivo.
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Molotkov, Andrei, John W. Castrillon, Sreevidya Santha, Paul E. Harris, David K. Leung, Akiva Mintz i Patrick Carberry. "The Radiolabeling of a Gly-Sar Dipeptide Derivative with Flourine-18 and Its Use as a Potential Peptide Transporter PET Imaging Agent". Molecules 25, nr 3 (2.02.2020): 643. http://dx.doi.org/10.3390/molecules25030643.
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We have developed a novel fluorine-18 radiotracer, dipeptide 1, radiolabeled in two steps from mesylate 3. The initial radiolabeling is achieved in a short reaction time (10 min) and purified through solid-phase extraction (SPE) with modest radiochemical yields (rcy = 10 ± 2%, n = 5) in excellent radiochemical purity (rcp > 99%, n = 5). The de-protection of the tert-butyloxycarbonyl (Boc) and trityl group was achieved with mild heating under acidic conditions to provide 18F-tagged dipeptide 1. Preliminary analysis of 18F-dipeptide 1 was performed to confirm uptake by peptide transporters (PepTs) in human pancreatic carcinoma cell lines Panc1, BxPC3, and ASpc1, which are reported to express the peptide transporter 1 (PepT1). Furthermore, we confirmed in vivo uptake of 18F-dipeptide tracer 1 using microPET/CT in mice harboring subcutaneous flank Panc1, BxPC3, and Aspc1 tumors. In conclusion, we have established the radiolabeling of dipeptide 1 with fluoride-18, and demonstrated its potential as an imaging agent which may have clinical applications for the diagnosis of pancreatic carcinomas.
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Shan, Daming, Oliver W. Press, Theta T. Tsu, Martha S. Hayden i Jeffrey A. Ledbetter. "Characterization of scFv-Ig Constructs Generated from the Anti-CD20 mAb 1F5 Using Linker Peptides of Varying Lengths". Journal of Immunology 162, nr 11 (1.06.1999): 6589–95. http://dx.doi.org/10.4049/jimmunol.162.11.6589.
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Abstract The heavy (VH) and light (VL) chain variable regions of the murine anti-human CD20 mAb 1F5 were cloned, and four single-chain Ab (scFv) molecules were constructed using linker peptides of variable lengths to join the VH and VL domains. Three constructs were engineered using linker peptides of 15, 10, and 5 aa residues consisting of (GGGGS)3, (GGGGS)2, and (GGGGS)1 sequences, respectively, whereas the fourth was prepared by joining the VH and VL domains directly. Each construct was fused to a derivative of human IgG1 (hinge plus CH2 plus CH3) to facilitate purification using staphylococcal protein A. The aggregation and CD20 binding properties of these four 1F5 scFv-Ig derivatives produced were investigated. Both size-exclusion HPLC column analysis and Western blots of proteins subjected to nonreducing SDS-PAGE suggested that all four 1F5 scFv-Ig were monomeric with m.w. of ∼55 kDa. The CD20 binding properties of the four 1F5 scFv-Ig were studied by ELISA and flow cytometry. The 1F5 scFv-Ig with the 5-aa linker (GS1) demonstrated significantly superior binding to CD20-expressing target cells, compared with the other scFv-Ig constructs. Scatchard analysis of the radiolabeled monovalent GS1 scFv-Ig revealed a binding avidity of 1.35 × 108 M−1 compared with an avidity of 7.56 × 108 M−1 for the native bivalent 1F5 Ab. These findings suggest that the GS1 scFv-Ig with a short linker peptide of ∼5 aa is the best of the engineered constructs for future studies.
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Saugar, José María, María Jesús Rodríguez-Hernández, Beatriz G. de la Torre, María Eugenia Pachón-Ibañez, María Fernández-Reyes, David Andreu, Jerónimo Pachón i Luis Rivas. "Activity of Cecropin A-Melittin Hybrid Peptides against Colistin-Resistant Clinical Strains of Acinetobacter baumannii: Molecular Basis for the Differential Mechanisms of Action". Antimicrobial Agents and Chemotherapy 50, nr 4 (kwiecień 2006): 1251–56. http://dx.doi.org/10.1128/aac.50.4.1251-1256.2006.
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ABSTRACT Acinetobacter baumannii has successfully developed resistance against all common antibiotics, including colistin (polymyxin E), the last universally active drug against this pathogen. The possible widespread distribution of colistin-resistant A. baumannii strains may create an alarming clinical situation. In a previous work, we reported differences in lethal mechanisms between polymyxin B (PXB) and the cecropin A-melittin (CA-M) hybrid peptide CA(1-8)M(1-18) (KWKLFKKIGIGAVLKVLTTGLPALIS-NH2) on colistin-susceptible strains (J. M. Saugar, T. Alarcón, S. López-Hernández, M. López-Brea, D. Andreu, and L. Rivas, Antimicrob. Agents Chemother. 46:875-878, 2002). We now demonstrate that CA(1-8)M(1-18) and three short analogues, namely CA(1-7)M(2-9) (KWKLFKKIGAVLKVL-NH2), its Nα-octanoyl derivative (Oct-KWKLFKKIGAVLKVL-NH2), and CA(1-7)M(5-9) (KWKLLKKIGAVLKVL-NH2) are active against two colistin-resistant clinical strains. In vitro, resistance to colistin sulfate was targeted to the outer membrane, as spheroplasts were equally lysed by a given peptide, regardless of their respective level of colistin resistance. The CA-M hybrids were more efficient than colistin in displacing lipopolysaccharide-bound dansyl-polymyxin B from colistin-resistant but not from colistin-susceptible strains. Similar improved performance of the CA-M hybrids in permeation of the inner membrane was observed, regardless of the resistance pattern of the strain. These results argue in favor of a possible use of CA-M peptides, and by extension other antimicrobial peptides with similar features, as alternative chemotherapy in colistin-resistant Acinetobacter infections.
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Hinrichsen, M., M. Lenz, J. M. Edwards, O. K. Miller, S. G. J. Mochrie, P. S. Swain, U. Schwarz-Linek i L. Regan. "A new method for post-translationally labeling proteins in live cells for fluorescence imaging and tracking". Protein Engineering, Design and Selection 30, nr 12 (1.12.2017): 771–80. http://dx.doi.org/10.1093/protein/gzx059.
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AbstractWe present a novel method to fluorescently label proteins, post-translationally, within live Saccharomycescerevisiae. The premise underlying this work is that fluorescent protein (FP) tags are less disruptive to normal processing and function when they are attached post-translationally, because target proteins are allowed to fold properly and reach their final subcellular location before being labeled. We accomplish this post-translational labeling by expressing the target protein fused to a short peptide tag (SpyTag), which is then covalently labeled in situ by controlled expression of an open isopeptide domain (SpyoIPD, a more stable derivative of the SpyCatcher protein) fused to an FP. The formation of a covalent bond between SpyTag and SpyoIPD attaches the FP to the target protein. We demonstrate the general applicability of this strategy by labeling several yeast proteins. Importantly, we show that labeling the membrane protein Pma1 in this manner avoids the mislocalization and growth impairment that occur when Pma1 is genetically fused to an FP. We also demonstrate that this strategy enables a novel approach to spatiotemporal tracking in single cells and we develop a Bayesian analysis to determine the protein’s turnover time from such data.
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Bojarska, Joanna, Martin Breza, Milan Remko, Malgorzata Czyz, Anna Gajos-Michniewicz, Michał Zimecki, Krzysztof Kaczmarek, Izabela D. Madura, Jakub M. Wojciechowski i Wojciech M. Wolf. "Structural and Biofunctional Insights into the Cyclo(Pro-Pro-Phe-Phe-) Scaffold from Experimental and In Silico Studies: Melanoma and Beyond". International Journal of Molecular Sciences 23, nr 13 (28.06.2022): 7173. http://dx.doi.org/10.3390/ijms23137173.
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Short peptides have great potential as safe and effective anticancer drug leads. Herein, the influence of short cyclic peptides containing the Pro-Pro-Phe-Phe sequence on patient-derived melanoma cells was investigated. Cyclic peptides such as cyclo(Leu-Ile-Ile-Leu-Val-Pro-Pro-Phe-Phe-), called CLA, and cyclo(Pro-homoPro-β3homoPhe-Phe-), called P11, exert the cytotoxic and the cytostatic effects in melanoma cells, respectively. CLA was the most active peptide as it reduced the viability of melanoma cells to 50% of control at about 10 µM, whereas P11 at about 40 µM after 48 h incubation. Interestingly, a linear derivative of P11 did not induce any effect in melanoma cells confirming previous studies showing that cyclic peptides exert better biological activity compared to their linear counterparts. According to in silico predictions, cyclic tetrapeptides show a better pharmacokinetic and toxic profile to humans than CLA. Notably, the spatial structure of those peptides containing synthetic amino acids has not been explored yet. In the Cambridge Structural Database, there is only one such cyclic tetrapeptide, cyclo((R)-β2homoPhe-D-Pro-Lys-Phe-), while in the Protein Data Bank—none. Therefore, we report the first crystal structure of cyclo(Pro-Pro-β3homoPhe-Phe-), denoted as 4B8M, a close analog of P11, which is crucial for drug discovery. Comparative molecular and supramolecular analysis of both structures was performed. The DFT findings revealed that 4B8M is well interpreted in the water solution. The results of complex Hirshfeld surface investigations on the cooperativity of interatomic contacts in terms of electrostatic and energetic features are provided. In short, the enrichment ratio revealed O…H/H…O and C…H/H…C as privileged intercontacts in the crystals in relation to basic and large supramolecular H-bonding synthon patterns. Furthermore, the ability of self-assemble 4B8M leading to a nanotubular structure is also discussed.
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Giribaldi, Giuliana, Mauro Prato, Daniela Ulliers, Valentina Gallo, Evelin Schwarzer, Oskar B. Akide-Ndunge, Elena Valente, Silvia Saviozzi, Raffaele A. Calogero i Paolo Arese. "Involvement of Inflammatory Chemokines in Survival of Human Monocytes Fed with Malarial Pigment". Infection and Immunity 78, nr 11 (23.08.2010): 4912–21. http://dx.doi.org/10.1128/iai.00455-10.
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ABSTRACT Hemozoin (HZ)-fed monocytes are exposed to strong oxidative stress, releasing large amounts of peroxidation derivatives with subsequent impairment of numerous functions and overproduction of proinflammatory cytokines. However, the histopathology at autopsy of tissues from patients with severe malaria showed abundant HZ in Kupffer cells and other tissue macrophages, suggesting that functional impairment and cytokine production are not accompanied by cell death. The aim of the present study was to clarify the role of HZ in cell survival, focusing on the qualitative and temporal expression patterns of proinflammatory and antiapoptotic molecules. Immunocytochemical and flow cytometric analyses showed that the long-term viability of human monocytes was unaffected by HZ. Short-term analysis by macroarray of a complete panel of cytokines and real-time reverse transcription (RT)-PCR experiments showed that HZ immediately induced interleukin-1β (IL-1β) gene expression, followed by transcription of eight additional chemokines (IL-8, epithelial cell-derived neutrophil-activating peptide 78 [ENA-78], growth-regulated oncogene α [GROα], GROβ, GROγ, macrophage inflammatory protein 1α [MIP-1α], MIP-1β, and monocyte chemoattractant protein 1 [MCP-1]), two cytokines (tumor necrosis factor alpha [TNF-α] and IL-1receptor antagonist [IL-1RA]), and the cytokine/chemokine-related proteolytic enzyme matrix metalloproteinase 9 (MMP-9). Furthermore, real-time RT-PCR showed that 15-HETE, a potent lipoperoxidation derivative generated by HZ through heme catalysis, recapitulated the effects of HZ on the expression of four of the chemokines. Intermediate-term investigation by Western blotting showed that HZ increased expression of HSP27, a chemokine-related protein with antiapoptotic properties. Taken together, the present data suggest that apoptosis of HZ-fed monocytes is prevented through a cascade involving 15-HETE-mediated upregulation of IL-1β transcription, rapidly sustained by chemokine, TNF-α, MMP-9, and IL-1RA transcription and upregulation of HSP27 protein expression.
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Oliveira, Aline Cristina, Marcos Barrouin Melo, Daisy Motta-Santos, A. Augusto Peluso, Fernando Souza-Neto, Rafaela F. da Silva, Jonathas F. Q. Almeida i in. "Genetic deletion of the alamandine receptor MRGD leads to dilated cardiomyopathy in mice". American Journal of Physiology-Heart and Circulatory Physiology 316, nr 1 (1.01.2019): H123—H133. http://dx.doi.org/10.1152/ajpheart.00075.2018.
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We have recently described a new peptide of the renin-angiotensin system, alamandine, a derivative of angiotensin-(1–7). Mas-related G protein-coupled receptor member D (MrgD) was identified as its receptor. Although similar cardioprotective effects of alamandine to those of angiotensin-(1–7) have been described, the significance of this peptide in heart function is still elusive. We aimed to evaluate the functional role of the alamandine receptor MrgD in the heart using MrgD-deficient mice. MrgD was localized in cardiomyocytes by immunofluorescence using confocal microscopy. High-resolution echocardiography was performed in wild-type and MrgD-deficient mice (2 and 12 wk old) under isoflurane anesthesia. Standard B-mode images were obtained in the right and left parasternal long and short axes for morphological and functional assessment and evaluation of cardiac deformation. Additional heart function evaluation was performed using Langendorff isolated heart preparations and inotropic measurements of isolated cardiomyocytes. Immunofluorescence indicated that the MrgD receptor is expressed in cardiomyocytes, mainly in the membrane and perinuclear and nuclear regions. Echocardiography showed left ventricular remodeling and severe dysfunction in MrgD-deficient mice. Strikingly, MrgD-deficient mice presented a pronounced dilated cardiomyopathy with a marked decrease in systolic function. Echocardiographic changes were supported by the data obtained in isolated hearts and inotropic measurements in cardiomyocytes. Our data add new evidence for a major role for alamandine/MrgD in the heart. Furthermore, our results indicate that we have identified a new gene implicated in dilated cardiomyopathy, unveiling a new target for translational approaches aimed to treat heart diseases. NEW & NOTEWORTHY The renin-angiotensin system is a key target for cardiovascular therapy. We have recently identified a new vasodepressor/cardioprotective angiotensin, alamandine. Here, we unmasked a key role for its receptor, Mas-related G protein-coupled receptor member D (MrgD), in heart function. The severe dilated cardiomyopathy observed in MrgD-deficient mice warrants clinical and preclinical studies to unveil its potential use in cardiovascular therapy. Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/mrgd-deficiency-leads-to-dilated-cardiomyopathy/ .
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Bingle, Wade H., Harry D. Kurtz Jr. i John Smit. "An ''all-purpose" cellulase reporter for gene fusion studies and application to the paracrystalline surface (S)-layer protein of Caulobacter crescentus". Canadian Journal of Microbiology 39, nr 1 (1.01.1993): 70–80. http://dx.doi.org/10.1139/m93-010.
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The secreted endoglucanase (CenA) from the Gram-positive bacterium Cellulomonas fimi and a deletion derivative (ΔCenA) lacking the N-terminal leader peptide of native CenA were used to explore the potential of ΔCenA as a reporter molecule in Caulobacter crescentus. Expression of cenA in C. crescentus yielded extracellular endoglucanase activity, suggesting that the N-terminal leader peptide of CenA could direct the enzyme to the periplasm where it subsequently leaked into the medium. In contrast, expression of ΔcenA yielded only cell-associated endoglucanase activity; this suggested that the enzyme retained activity in the C. crescentus cytoplasm. Using the putative cytoplasmic and periplasmic forms of ΔCenA as markers, a simple assay for periplasmic ΔCenA hybrids was developed. This assay indicated that ΔCenA activity was largely independent of cellular location. To facilitate the use of ΔCenA as a reporter, a broad host range translational fusion vector (pEC215) incorporating ΔcenA was constructed. This vector was used to investigate factors important to the expression of the gene (rsaA) encoding the paracrystalline surface protein (S-layer) of the bacterium. It was found that altering the 5′ untranslated region of the rsaA mRNA reduced gene expression by 70%. One rsaA:ΔcenA gene fusion resulting from these experiments that incorporated only rsaA translation initiation information was further modified to serve as a general reporter for creating transcriptional gene fusions with other promoters. Gene fusions between alkaline phosphatase (phoA) and either cenA or lacZ were used to supplement information about RsaA secretion derived from rsaA:phoA gene fusions. It was found that linkage of the N-terminal leader peptide of CenA to PhoA yielded 50–100 times more cell-associated PhoA activity in C. crescentus than linkage of the RsaA N terminus. Taken together, these experiments indicated that ΔCenA was useful for tagging proteins localized to the cytoplasm, exported to the periplasm, or secreted from the cell, as well as for monitoring events in the cytoplasm such as examining factors important to the level of gene expression. Further, because ΔCenA was active in all cell compartments, it could be used to estimate the efficiency of hybrid protein export-secretion from enzyme activity measurements alone. In short, ΔCenA possessed many of the attributes of an "all-purpose" reporter.Key words: gene fusions, protein secretion, cellulase, alkaline phosphatase, Caulobacter crescentus.
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Pfister, Joachim, Roland Bata, Isabella Hubmann, Anton Amadeus Hörmann, Fabio Gsaller, Hubertus Haas i Clemens Decristoforo. "Siderophore Scaffold as Carrier for Antifungal Peptides in Therapy of Aspergillus fumigatus Infections". Journal of Fungi 6, nr 4 (15.12.2020): 367. http://dx.doi.org/10.3390/jof6040367.
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Antifungal resistance of human fungal pathogens represents an increasing challenge in modern medicine. Short antimicrobial peptides (AMP) display a promising class of antifungals with a different mode of action, but lack target specificity and metabolic stability. In this study the hexapeptide PAF26 (Ac-dArg-dLys-dLys-dTrp-dPhe-dTrp-NH2) and the three amino acid long peptide NLF (H2N-Asn-Leu-dPhe-COOH) were coupled to diacetylfusarinine C (DAFC), a derivative of the siderophore triacetylfusarinine C (TAFC) of Aspergillus fumigatus, to achieve targeted delivery for treatment of invasive aspergillosis. Conjugated compounds in various modifications were labelled with radioactive gallium-68 to perform in vitro and in vivo characterizations. LogD, serum stability, uptake- growth promotion- and minimal inhibitory concentration assays were performed, as well as in vivo stability tests and biodistribution in BALB/c mice. Uptake and growth assays revealed specific internalization of the siderophore conjugates by A. fumigatus. They showed a high stability in human serum and also in the blood of BALB/c mice but metabolites in urine, probably due to degradation in the kidneys. Only PAF26 showed growth inhibition at 8 µg/ml which was lost after conjugation to DAFC. Despite their lacking antifungal activity conjugates based on a siderophore scaffold have a potential to provide the basis for a new class of antifungals, which allow the combination of imaging by using PET/CT with targeted treatment, thereby opening a theranostic approach for personalized therapy.
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Arend, Sandra M., Anrik C. F. Engelhard, Gertjan Groot, Kirsten de Boer, Peter Andersen, Tom H. M. Ottenhoff i Jaap T. van Dissel. "Tuberculin Skin Testing Compared with T-Cell Responses to Mycobacterium tuberculosis-Specific and Nonspecific Antigens for Detection of Latent Infection in Persons with Recent Tuberculosis Contact". Clinical Diagnostic Laboratory Immunology 8, nr 6 (1.11.2001): 1089–96. http://dx.doi.org/10.1128/cdli.8.6.1089-1096.2001.
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ABSTRACT The tuberculin skin test (TST) is used for the identification of latent tuberculosis (TB) infection (LTBI) but lacks specificity inMycobacterium bovis BCG-vaccinated individuals, who constitute an increasing proportion of TB patients and their contacts from regions where TB is endemic. In previous studies, T-cell responses to ESAT-6 and CFP-10, M. tuberculosis-specific antigens that are absent from BCG, were sensitive and specific for detection of active TB. We studied 44 close contacts of a patient with smear-positive pulmonary TB and compared the standard screening procedure for LTBI by TST or chest radiographs with T-cell responses toM. tuberculosis-specific and nonspecific antigens. Peripheral blood mononuclear cells were cocultured with ESAT-6, CFP-10, TB10.4 (each as recombinant antigen and as a mixture of overlapping synthetic peptides), M. tuberculosis sonicate, purified protein derivative (PPD), and short-term culture filtrate, using gamma interferon production as the response measure. LTBI screening was by TST in 36 participants and by chest radiographs in 8 persons. Nineteen contacts were categorized as TST negative, 12 were categorized as TST positive, and 5 had indeterminate TST results. Recombinant antigens and peptide mixtures gave similar results. Responses to TB10.4 were neither sensitive nor specific for LTBI. T-cell responses to ESAT-6 and CFP-10 were less sensitive for detection of LTBI than those to PPD (67 versus 100%) but considerably more specific (100 versus 72%). The specificity of the TST or in vitro responses to PPD will be even less when the proportion of BCG-vaccinated persons among TB contacts evaluated for LTBI increases.
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Antsiferov, Oleg V., Roman F. Cherevatenko, Mikhail V. Korokin, Vladimir V. Gureev, Anastasia V. Gureeva, Mariya A. Zatolokina, Elena V. Avdeyeva, Lyudmila A. Zhilinkova i Inga M. Kolesnik. "A new EPOR/CD131 heteroreceptor agonist EP-11-1: a neuroprotective effect in experimental traumatic brain injury". Research Results in Pharmacology 7, nr 4 (9.10.2021): 1–9. http://dx.doi.org/10.3897/rrpharmacology.7.75301.
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Introduction: EP-11-1 (UEHLERALNSS) is a short-chain erythropoietin derivative without have erythropoietic activity. It was created by modifying a peptide mimicking the spatial structure of the erythropoietin a-helix B pHBSP. One of the promising directions of its administration is the correction of morphofunctional disorders that occur in traumatic brain injury (TBI). Materials and methods: The study was performed in 160 male Wistar rats, weighing 180–200 g.TBI was simulated using the drop-weight method. To assess the emerging morphofunctional disorders and a degree of their correction, we used the severity of neurological deficit, indicators of locomotor activity and exploration, a marker of brain injury S100B and morphological examination. Results and discussion: The combined administration of a new EPOR/CD131 heteroreceptor agonist EP-11-1 with citicoline and trimetazidine led to a more pronounced correction of the neurological deficit when compared not only to the group of the ”untreated” animals, but also to the groups of animals to which these drugs had been administered as monotherapy (p < 0.05). The same tendency was also observed in the study of locomotor activity and exploration. A biochemical study showed that the administration of all three combinations led to a statistically significant (p < 0.05) decrease in the S-100B concentration compared not only to the group of “untreated” animals, but also to the groups of animals to which these drugs had been administered as a monotherapy. Conclusion: The results of the conducted experiments prove the most pronounced positive dynamics in the combined administration of the new EPOR/CD131 heteroreceptor agonist EP-11-1with citicoline and trimetazidine.
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Gollan, Timothy J., i Michael R. Green. "Selective Targeting and Inducible Destruction of Human Cancer Cells by Retroviruses with Envelope Proteins Bearing Short Peptide Ligands". Journal of Virology 76, nr 7 (1.04.2002): 3564–69. http://dx.doi.org/10.1128/jvi.76.7.3564-3569.2002.
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ABSTRACT In the accompanying study, we show how retroviral tropism can be redirected by insertion of short peptide ligands at multiple locations in envelope. Here we use this approach to selectively target and destroy human cancer cells. Many cancer cells overexpress specific cell surface receptors. We have generated Moloney murine leukemia virus (MLV) envelope derivatives bearing short peptide ligands for gastrin-releasing protein (GRP) and human epidermal growth factor receptors. Pseudotyped viruses containing these chimeric envelope derivatives selectively transduce human cancer cell lines that overexpress the cognate receptor. A retrovirus targeting the GRP receptor can deliver the thymidine kinase gene to human melanoma and breast cancer cells, which are killed by the subsequent addition of ganciclovir. Collectively, our results demonstrate that short peptide ligands inserted at appropriate locations in MLV envelope can selectively target retroviruses to human cancer cells and deliver a therapeutically relevant gene.
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Moskowitz, Keith A., Josh Dee, Jason Barnidge, Ruth Sum, David Ho, Alan S. Rudolph i Cindy S. Orser. "Hemostatic Properties of Infusible Trehalose-Stabilized Lyophilized Platelet Derivatives." Blood 104, nr 11 (16.11.2004): 834. http://dx.doi.org/10.1182/blood.v104.11.834.834.
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Abstract Availability of platelet concentrates for treatment of bleeding associated with thrombocytopenia, trauma, or drug-induced coagulopathies is problematic due to the short 5 day platelet storage time and because platelets require controlled shaking at ambient temperature in order to remain viable, a condition which augments bacterial growth. To address the platelet availability problem we expanded upon trehalose cryo-preservation technology to create a lyophilized hemostatic platelet derivative. Washed platelets were stabilized by accumulation of 5–10 mM intracellular trehalose via fluid phase endocytosis then formulated with excipients and lyophilized. Lyophilized platelets were instantaneously rehydrated with > 90% recovery and were stable for at least 3–6 months at ambient temperatures. Rehydrated (RH) platelets responded quantitatively to α-and γ-thrombin and ristocetin by transmittance aggregometry and were partially agglutinated by collagen as judged by aggregometry and single cell counting using the Platelet Works® system. RH platelets co-aggregated in a dose dependent manner when mixed with fresh autologous platelets during collagen-induced activation. Aggregation response to low-dose thrombin and collagen was inhibited by the GPIIb/IIIa antagonist RGDS and by EGTA. RH platelets were quantitatively incorporated into fibrin clots and elicited platelet-dependent fibrin-clot retraction ~ 60% as well as fresh platelets. RH platelets were similar in size to fresh and had less than 25% submicron particles as judged by electronic particle counting and flow cytometry scatter profiles. RH platelets were partially activated upon rehydration as judged by anti P-selectin and anti-LAMP-3 binding, yet GPIIb/IIIa remained in a resting conformation, as judged by a lack of PAC-1 binding. GPIIb/IIIa receptors were present as judged by the binding of complex-dependent (clone 5B12) and function-blocking (clone P2) antibodies. RH platelets also contained intact GPIbα as judged by binding of the function-blocking MoAb AN51. Function of GPIIb/IIIa and collagen receptors on RH platelets was further demonstrated as RH platelets adhered to immobilized fibrinogen and collagen in the absence of added agonists and in a dose-dependent manner. Moreover, RH platelets exhibited a two-fold increase in platelet procoagulant activity in the presence of thrombin receptor agonist peptide SFLLRN as judged by Annexin-V binding. Procoagulant and hemostatic activity was further demonstrated as RH platelets accelerated the clotting of recalcified whole thrombocytopenic blood in a dose-dependent manner similarly to fresh platelets. Lastly, RH platelets corrected the coagulopathy induced by contact pathway inhibition with aprotinin during the recalcification of citrated whole blood. The technology has been scaled to single donor platelet aphaeresis units, equivalent to a standard transfusion dose. Preclinical animal models of safety, efficacy, and circulation persistence are currently being evaluated. In summary, trehalose- stabilized lyophilized platelet derivatives contain numerous in vitro hemostatic properties and may offer an attractive alternative to fresh platelet transfusions when the latter are indicated yet unavailable.
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Vakhrushev, Alexander V., Dmitry A. Gruzdev, Alexander M. Demin, Galina L. Levit i Victor P. Krasnov. "Synthesis of Novel Carborane-Containing Derivatives of RGD Peptide". Molecules 28, nr 8 (14.04.2023): 3467. http://dx.doi.org/10.3390/molecules28083467.
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Short peptides containing the Arg-Gly-Asp (RGD) fragment can selectively bind to integrins on the surface of tumor cells and are attractive transport molecules for the targeted delivery of therapeutic and diagnostic agents to tumors (for example, glioblastoma). We have demonstrated the possibility of obtaining the N- and C-protected RGD peptide containing 3-amino-closo-carborane and a glutaric acid residue as a linker fragment. The resulting carboranyl derivatives of the protected RGD peptide are of interest as starting compounds in the synthesis of unprotected or selectively protected peptides, as well as building blocks for preparation of boron-containing derivatives of the RGD peptide of a more complex structure.
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Kaur, Harsimran, i Sangita Roy. "Designing aromatic N-cadherin mimetic short-peptide-based bioactive scaffolds for controlling cellular behaviour". Journal of Materials Chemistry B 9, nr 29 (2021): 5898–913. http://dx.doi.org/10.1039/d1tb00598g.
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Zelder, Felix. "Modified vitamin B12 derivatives with a peptide backbone for biomimetic studies and medicinal applications". Journal of Porphyrins and Phthalocyanines 22, nr 07 (lipiec 2018): 535–41. http://dx.doi.org/10.1142/s108842461830001x.
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This short review highlights the author’s group research on modified vitamin B[Formula: see text] derivatives with a peptide backbone as (1) inhibitors of B[Formula: see text]-dependent enzymes and as (2) models of cofactor B[Formula: see text]-protein complexes.
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Ciura, Krzesimir, Natalia Ptaszyńska, Hanna Kapica, Monika Pastewska, Anna Łęgowska, Krzysztof Rolka, Wojciech Kamysz, Wiesław Sawicki i Katarzyna E. Greber. "Can Immobilized Artificial Membrane Chromatography Support the Characterization of Antimicrobial Peptide Origin Derivatives?" Antibiotics 10, nr 10 (12.10.2021): 1237. http://dx.doi.org/10.3390/antibiotics10101237.
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The emergence and spread of multiple drug-resistant bacteria strains caused the development of new antibiotics to be one of the most important challenges of medicinal chemistry. Despite many efforts, the commercial availability of peptide-based antimicrobials is still limited. The presented study aims to explain that immobilized artificial membrane chromatography can support the characterization of antimicrobial peptides. Consequently, the chromatographic experiments of three groups of related peptide substances: (i) short cationic lipopeptides, (ii) citropin analogs, and (iii) conjugates of ciprofloxacin and levofloxacin, with a cell-penetrating peptide were discussed. In light of the discussion of the mechanisms of action of these compounds, the obtained results were interpreted.
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Lagadinou, Eleni D., Panagiotis G. Ziros, Olga A. Tsopra, Kostas Dimas, Panagiotis Pantazis, Alexandros Spyridonidis i Nicholas C. Zoumbos. "c-Jun N-Terminal Kinase (JNK) Activation Failure Confers a New Mechanism of Anthracycline Resistance in Acute Myeloid Leukemia (AML)." Blood 110, nr 11 (16.11.2007): 2377. http://dx.doi.org/10.1182/blood.v110.11.2377.2377.
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Abstract Chemotherapy resistance remains a major challenge in the treatment of acute myeloid leukemia (AML). Besides the P-glycoprotein efflux of chemotherapeutics, additional cellular factors may contribute to drug resistance in AML. c- Jun N-terminal Kinase (JNK) is a protein kinase activated after exposure of cells to chemotherapeutic agents. Recently, studies in solid tumours have associated chemoresistance with failure of cancer cells to activate JNK. We asked whether drug resistance in AML is also attributed to intrinsic failure of the AML blasts to activate JNK. In vitro treatment of U937 AML cell line with anthracyclines induced a rapid and robust JNK phosphorylation and apoptosis. In contrast, the anthracyline-resistant derivative U937R cells showed no JNK activation after exposure to anthracyclines, also at doses that resulted in high accumulation of the drug within the cells. Inhibition of JNK in drug-sensitive U937 cells made them resistant to anthracyclines. First, JNK1-siRNA transfected U937 cells exhibited a 50.4% and 61.3% reduced daunorubicin- (DNR, 1μM 24hr) and doxorubicin- (DOX, 1.5 μM 24hr) induced apoptosis respectively; as compared to empty vector or untransfected U937 cells (P< 0.001). Second, pretreatment of U937 cells with the 420116 cell-permeable JNK inhibitor (1 μM) reduced to a less but yet significant extent DNR-induced apoptosis as compared to cells treated with a negative control peptide (P = 0.013<0.05). On the other hand, selective restoration of the inactive JNK pathway in resistant U937R cells by transfection with a mutant form of the SEK1/MKK4 upstream activator of JNK sensitized U937R cells to anthracyclines, compared to empty vector transfected cells (3.3-fold increase in DNR-induced apoptosis, 1μM DNR, 24hr and 3.1-fold increase in DOX-induced apoptosis, 1.5μM DOX, 24hr). Furthermore, we assessed the activation of JNK pathway in 29 primary AML bone marrow samples after short term (30-60 min) in vitro exposure to DNR (1 μM) and correlated it with clinical data. We found a strong correlation between the in vitro pharmacodymanic changes of phospho-JNK levels in AML primary blasts and the response of the AML patients to standard induction chemotherapy (P = 0.012). In addition, the drug-induced JNK activation pattern correlated with AML evolving from antecedent MDS (P = 0.017) and patient age (P = 0.046). In summary, our in vitro and in vivo results suggest that JNK activation failure is another mechanism of anthracycline resistance in AML. Elucidating the ultimate mechanisms leading to JNK suppression in chemoresistant AML may be of major therapeutic value.
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Gureev, Vladimir V., Mikhail V. Korokin, Ivan V. Golubev, Mikhail V. Pokrovsky, Adelaida V. Polyanskaya i Dmitriy B. Kuzmin. "Correction of functional disorders in ADMA-like preeclampsia with derivatives of the peptide imitating erythropoietin α-helix B". Курский научно-практический вестник «Человек и его здоровье», nr 2 (czerwiec 2020): 42–49. http://dx.doi.org/10.21626/vestnik/2020-2/06.
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Objective. The aim of the study is to investigate the correction of functional disorders in ADMA-like preeclampsia with derivatives of the peptide imitating erythropoietin α-helix B. Materials and methods. The study was performed in 120 white female Wistar rats weighing 250-300 g. ADMA-like preeclampsia was used as experimental preeclampsia. To assess the effectiveness of the pharmacological agents used, blood pressure, microcirculation in the placenta, and proteinuria were recorded, the content of final NO metabolites in the blood plasma was determined, and the coefficient of endothelial dysfunction was calculated. 50 μg / kg polypeptides (P-αB3 and P-αB4) were used as pharmacological agents, obtained by attaching to the original 11-amino acid peptide PHBSP [PubChem CID: 91810664], which is the amino acid chain Pyr-Glu-Gln-Leu-Glu-Arg-Ala-Leu-Asn-Ser-Ser (QEQLERALNSS) of KGD group from different ends of the chain. Results. The use of the studied derivatives of peptide imitating erythropoietin α-helix B with ADMA-like preeclampsia leads to a pronounced correction of disorders. The greatest effect was observed with the introduction of the peptide with the laboratory code P-αB4. A significant decrease in systolic and diastolic pressure was noted, respectively, improved microcirculation in the placenta, restoration of the NO-synthesizing function of the endothelium, and a decrease in proteinuria. Conclusion. The results obtained indicate the prospect of further research on the effectiveness of short-chain derivatives of erythropoietin imitating its α-helix B for the correction of functional disorders in preeclampsia.
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Gollan, Timothy J., i Michael R. Green. "Redirecting Retroviral Tropism by Insertion of Short, Nondisruptive Peptide Ligands into Envelope". Journal of Virology 76, nr 7 (1.04.2002): 3558–63. http://dx.doi.org/10.1128/jvi.76.7.3558-3563.2002.
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ABSTRACT A potentially powerful approach for in vivo gene delivery is to target retrovirus to specific cells through interactions between cell surface receptors and appropriately modified viral envelope proteins. Previously, relatively large (>100 residues) protein ligands to cell surface receptors have been inserted at or near the N terminus of retroviral envelope proteins. Although viral tropism could be altered, the chimeric envelope proteins lacked full activity, and coexpression of wild-type envelope was required for production of transducing virus. Here we analyze more than 40 derivatives of ecotropic Moloney murine leukemia virus (MLV) envelope, containing insertions of short RGD-containing peptides, which are ligands for integrin receptors. In many cases pseudotyped viruses containing only the chimeric envelope protein could transduce human cells. The precise location, size, and flanking sequences of the ligand affected transduction specificity and efficiency. We conclude that retroviral tropism can be rationally reengineered by insertion of short peptide ligands and without the need to coexpress wild-type envelope.
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Tivari, Sunil R., Siddhant V. Kokate, Enrique Delgado-Alvarado, Manoj S. Gayke, Amol Kotmale, Harun Patel, Iqrar Ahmad i in. "A novel series of dipeptide derivatives containing indole-3-carboxylic acid conjugates as potential antimicrobial agents: the design, solid phase peptide synthesis, in vitro biological evaluation, and molecular docking study". RSC Advances 13, nr 35 (2023): 24250–63. http://dx.doi.org/10.1039/d3ra04100j.
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A new library of peptide-heterocycle hybrids consisting of an indole-3-carboxylic acid constituent conjugated with short dipeptide motifs was designed and synthesized by using the solid phase peptide synthesis methodology.
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Fu, Y. X., M. Vollmer, H. Kalataradi, K. Heyborne, C. Reardon, C. Miles, R. O'Brien i W. Born. "Structural requirements for peptides that stimulate a subset of gamma delta T cells." Journal of Immunology 152, nr 4 (15.02.1994): 1578–88. http://dx.doi.org/10.4049/jimmunol.152.4.1578.
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Abstract Hybridomas representing the V gamma 1-positive subset of murine gamma delta T cells secrete lymphokines in response to synthetic peptides representing a short segment of the mycobacterial 60-kDa heat shock protein (HSP-60). Here we show the TCR dependency of this response by transfection of productively rearranged TCR genes derived from an HSP-60 reactive gamma delta T cell hybridoma. We also have defined structural requirements for the stimulatory peptide. The smallest HSP-60 peptide capable of stimulating these hybridomas is seven amino acids long, representing positions 181-187, and having the sequence FGLQLEL. Amino acid-substituted derivatives of this peptide, and another containing the same core, p180-190, revealed amino acids essential for stimulatory activity. Phenylalanine in position 181 and leucine in position 183 seem to be required for stimulation of all HSP-60 reactive cells, whereas others are only required by some. Clonal differences in the responses to these peptides provide indirect evidence for cognate TCR-peptide interactions. The smallest stimulatory peptide, p181-187, represents an area not well conserved among HSP-60 molecules of other species, and stimulates a mycobacteria-specific response unlike the earlier observed cross-reactive responses of the same hybridomas with longer HSP-60 peptides derived from mycobacteria and other species (our manuscript in preparation). We propose that the TCR-dependent multiclonal gamma delta T cell response to HSP-60 peptides and derivatives, which in some ways resembles superantigen responses and in other ways resembles responses to conventional Ag, may be a separate, third type of Ag response by T cells.
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Chattopadhyay, Shital Kumar, Subhankar Ghosh i Suman Sil. "Cross metathesis-mediated synthesis of hydroxamic acid derivatives". Beilstein Journal of Organic Chemistry 14 (17.12.2018): 3070–75. http://dx.doi.org/10.3762/bjoc.14.285.
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An alternative synthesis of α,ß-unsaturated hydroxamates via cross metathesis between a class-I olefin and N-benzyloxyacrylamide is reported. The reaction proceeds better in the presence of Grubbs’ second generation catalyst within short time and in good yields (57–85%) with a range of substrates. Subsequent hydrogenation of each of the CM products delivers the title compounds in moderate to very good yield (70–89%). An important demonstration of the protocol is the preparation of the unusual amino acid component of the bioactive cyclic peptide Chap-31.
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Tomizaki, Kin-ya, Tomomi Iori, Hideyasu Fukushima, Yasuhiro Nakabayashi, Yoshiki Matsumoto i Takahito Imai. "Tandem-Homodimer of a β-Sheet-Forming Short Peptide Inhibits Random-to-β Structural Transition of Its Original Monomer". Processes 8, nr 11 (8.11.2020): 1421. http://dx.doi.org/10.3390/pr8111421.
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There is an increasing interest in designing fibrillogenesis modulators for treating amyloid β (Aβ)-peptide-associated diseases. The use of Aβ fragment peptides and their derivatives, as well as nonpeptidyl natural products, is one promising approach to prevent Aβ fibrillation. In this study, we demonstrate that tandem-homodimers (TDs) of a β-sheet-forming short peptide in which the amino acid sequence is duplicated in series and joined via an amino alkanoic acid linker of different chain lengths, preventing the random-to-β structural transition of the original monomer. Ape5-TD, containing 5-amino pentanoate, most potently prevented this transition for at least five days by generating disordered aggregates with reduced tryptic stability. The linkers in the TDs generated this inhibitory activity, probably due to their bent conformations and hydrophobicity, appropriate for accommodating and twisting the monomers, resulting in irregular arrangements of the peptides. The present study could allow the design of a new class of protein/peptide fibrillogenesis modulators.
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Pouzar, Vladimír, i Ivan Černý. "Preparation of (17E)-3β-Hydroxyandrost-5-en-17-one (O-Carboxymethyl)oxime Derivatives with Short Peptide Chain". Collection of Czechoslovak Chemical Communications 59, nr 9 (1994): 2042–56. http://dx.doi.org/10.1135/cccc19942042.
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17-(O-Carboxymethyl)oxime (CMO) derivatives of 3β-acetoxy-, 3β-methoxymethoxy-, 3β-hydroxyandrost-5-en-17-one, and of -androst-4-ene-3,17-dione (IV - VI, XXIX) were prepared. Methods for the attachment of amino acids to the CMO group and for the peptide chain elongation were tested. The mixed anhydride method was used for linking the first amino acid unit (Gly, βAla, or Gly-Gly dipeptide), further units were added by the N-hydroxysuccinimide method. Compounds with one to four amino acids were prepared. This concept is suitable for the preparation of haptens with variable bridge length for the binding studies.
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Karamać, M., E. Sendrejová, A. Kosińska i D. Urminská. "Presence of ferulic acid in wheat glutenin fraction and its enzymatic hydrolysates – a short report". Czech Journal of Food Sciences 25, No. 6 (7.01.2008): 359–64. http://dx.doi.org/10.17221/751-cjfs.
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Three protein fractions: albumin-globulin, gliadin, and glutenin were extracted from wheat grains. Enzymatic hydrolysates were obtained from each fraction using trypsin, protease from <I>Bacillus subtilis</I> and Subtilisin Carlsberg. Ferulic acid was detected neither in albumin-globulin and gliadin fractions nor in their hydrolysates. The RP-HPLC and SE-HPLC chromatograms of the glutenin fraction and its hydrolysates revealed the presence of peaks originated from ferulic acid and ferulic acid derivative/complex. The content of ferulic acid in the glutenin fraction was 1.12 mg/g. During HPLC analysis, the peptide products of glutenin hydrolysis should be recorded at 220 nm because the peaks of the peptides recorded at 280 nm can be overlapped by the peaks of ferulic acid and its derivatives.
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Navon-Venezia, Shiri, Rina Feder, Leonid Gaidukov, Yehuda Carmeli i Amram Mor. "Antibacterial Properties of Dermaseptin S4 Derivatives with In Vivo Activity". Antimicrobial Agents and Chemotherapy 46, nr 3 (marzec 2002): 689–94. http://dx.doi.org/10.1128/aac.46.3.689-694.2002.
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ABSTRACT Derivatives of the cytotoxic peptide dermaseptin S4 have recently emerged as potential antimicrobial agents. Here, we report on the antibacterial properties of three derivatives with improved toxicity profiles: a 28-residues K4K20-S4 and two shorter versions, K4-S4(1-16) and K4-S4(1-13). The range of MICs of K4K20-S4 against clinical isolates of Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli were, respectively, 1 to 4, 1 to 4, and 1 to 16 μg/ml. MICs of the short derivatives were rather similar or two to fourfold higher. Each of the three peptides was rapidly bactericidal in vitro, reducing the number of viable CFU of either E. coli or S. aureus by 6 log units in 30 min or less. Compared with MSI-78 or PG-1, K4-S4(1-13) was at least as potent against bacteria (assessed at two MIC multiples) but displayed lesser toxicity against human erythrocytes. Serial passage in subinhibitory concentrations led to emergence of resistance to commercial antibiotics but not to the l- or d isomer of either of the dermaseptin derivatives. The short derivatives were further investigated for antibacterial activity in vivo, using a peritonitis model of mice infected with P. aeruginosa. Naive mice in the vehicle control group exhibited 75% mortality, compared to 18 or 36% mortality in mice that received a single intraperitoneal injection (4.5 mg/kg) of K4-S4(1-16) or K4-S4(1-13), respectively. In vivo bactericidal activity was confirmed in neutropenic mice, where intraperitoneal administration of K4-S4(1-16) reduced the number of viable CFU in a dose-dependent manner by >3 log units within 1 h of exposure, and this was sustained for at least 5 h. Overall, the data suggest that dermaseptin S4 derivatives could be useful in treatment of infections, including infections caused by multidrug-resistant bacteria.
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Albada, H. Bauke, Alina-Iulia Chiriac, Michaela Wenzel, Maya Penkova, Julia E. Bandow, Hans-Georg Sahl i Nils Metzler-Nolte. "Modulating the activity of short arginine-tryptophan containing antibacterial peptides with N-terminal metallocenoyl groups". Beilstein Journal of Organic Chemistry 8 (15.10.2012): 1753–64. http://dx.doi.org/10.3762/bjoc.8.200.
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A series of small synthetic arginine and tryptophan containing peptides was prepared and analyzed for their antibacterial activity. The effect of N-terminal substitution with metallocenoyl groups such as ferrocene (FcCO) and ruthenocene (RcCO) was investigated. Antibacterial activity in different media, growth inhibition, and killing kinetics of the most active peptides were determined. The toxicity of selected derivatives was determined against erythrocytes and three human cancer cell lines. It was shown that the replacement of an N-terminal arginine residue with a metallocenoyl moiety modulates the activity of WRWRW-peptides against Gram-positive and Gram-negative bacteria. MIC values of 2–6 µM for RcCO-W(RW)2 and 1–11 µM for (RW)3 were determined. Interestingly, W(RW)2-peptides derivatized with ferrocene were significantly less active than those derivatized with ruthenocene which have similar structural but different electronic properties, suggesting a major influence of the latter. The high activities observed for the RcCO-W(RW)2- and (RW)3-peptides led to an investigation of the origin of activity of these peptides using several important activity-related parameters. Firstly, killing kinetics of the RcCO-W(RW)2-peptide versus killing kinetics of the (RW)3 derivative showed faster reduction of the colony forming units for the RcCO-W(RW)2-peptide, although MIC values indicated higher activity for the (RW)3-peptide. This was confirmed by growth inhibition studies. Secondly, hemolysis studies revealed that both peptides did not lead to significant destruction of erythrocytes, even up to 500 µg/mL for (RW)3 and 250 µg/mL for RcCO-W(RW)2. In addition, toxicity against three human cancer cell lines (HepG2, HT29, MCF7) showed that the (RW)3-peptide had an IC50 value of ~140 µM and the RcW(RW)2 one of ~90 µM, indicating a potentially interesting therapeutic window. Both the killing kinetics and growth inhibition studies presented in this work point to a membrane-based mode of action for these two peptides, each having different kinetic parameters.
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Todorov, Petar, Stela Georgieva i Jana Tchekalarova. "Recent Synthesis, Characterization, and Pharmacological Evaluation of Multifunctional Hemorphins Containing Non-Natural Amino Acids with Potential Biological Importance". Pharmaceuticals 15, nr 11 (17.11.2022): 1425. http://dx.doi.org/10.3390/ph15111425.
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The endogenous hemorphins are bioactive peptides with activity on opioid receptors. They are extensively studied and summarized in numerous reviews. During the last decade, several research teams have synthesized, characterized, and pharmacologically evaluated synthetic hemorphin analogs containing unusual amino acids, D-amino acids, α-aminophosphonic acids, and their derivatives. The present review summarizes the current studies on short-chain synthetic hemorphin peptide derivates containing non-natural amino acids. This review focuses on the structure–activity relationship analysis, details on specific methods for their characterization, and the advantage of synthetic hemorphin analogs compared to endogenous peptides as potent biologically active compounds with a complex mechanism of action.
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Bianchini, Elsa, Steven J. Orcutt i Sriram Krishnaswamy. "Ratcheting between Two Distinct Conformations of Substrate Drives the Sequential Cleavage of Prothrombin by Prothrombinase." Blood 104, nr 11 (16.11.2004): 1717. http://dx.doi.org/10.1182/blood.v104.11.1717.1717.
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Abstract The conversion of human prothrombin to thrombin requires the cleavage of two peptide bonds. When catalyzed by prothrombinase, the reaction proceeds almost exclusively via initial cleavage at R320 followed by cleavage at R271 yielding meizothrombin (mIIa) as an intermediate. The scissile bonds are expected to be ~36 A apart in the zymogen. Yet, remarkably, evidence indicates that cleavage at these two sites is accomplished by a single type of exosite interaction that tethers the substrate to prothrombinase. The ability of prothrombinase to act on these spatially distinct sites, with such constraints, can be explained by a conformational change in the substrate following initial cleavage at R320. Cleavage at this site leads to internal salt bridge formation and a conformational transition to the proteinase. The role of the zymogen to proteinase transition in substrate cleavage was investigated by the use of a fully-carboxylated recombinant prothrombin derivative (IITAT) with the I-V-E sequence following R320 replaced with T-A-T. Thrombin produced by cleavage of IITAT exhibited ~0.2% of the catalytic activity observed with thrombin produced from wild type recombinant prothrombin (IIWT). IITAT can be cleaved at the R320 site but fails to undergo all subsequent conformational changes required for proteinase formation. SDS-PAGE and quantitative densitometry revealed that the action of prothrombinase on either IIWT or IITAT was consistent with ordered cleavage at R320 followed by cleavage at R271. The rates of consumption of IIWT and IITAT resulting from cleavage at R320 were equivalent. Cleavage at R320 in IITAT by prothrombinase is not detectably affected by the substituted P1′-P3′ sequence. The disappearance of IIWT was accompanied by a transient accumulation in mIIa that decreased to zero within 4 minutes while thrombin accumulated following a short delay. With IITAT, mIIa accumulated to higher levels and persisted for 45 minutes. Thrombin was produced with a lower rate and a longer delay phase. The findings imply a substantial decrease in the rate of the second cleavage reaction at R271 resulting from distant effects of the new P1′-P3′ residues following R320. The thrombin inhibitor, dansylarginine-N-(3-ethyl-1,5-pentanediyl)amide (DAPA) had no effect on the cleavage reactions in IIWT. However, increasing concentrations of DAPA as high as 400 μM were found to systematically enhance the rate of thrombin formation from IITAT by correcting defective cleavage at R271. The data are consistent with the interpretation that IITAT can be cleaved normally at R320 but subsequent accessibility and cleavage at R271 is reduced because of a defect in internal salt bridge formation and the conformational change associated with proteinase formation. Rescue of this defect by high concentrations of DAPA likely relates to the stabilization of a proteinase-like conformation in the intermediate produced by cleavage of IITAT at R320. Our findings suggest an important role for the zymogen to proteinase transition in determining the sequential action of prothrombinase on the two sites in prothrombin. We propose that exosite-dependent tethering of two distinct conformations of the substrate to prothrombinase drives the presentation of distantly positioned cleavage sites to the active site of the enzyme and accounts for the sequential cleavage of prothrombin.
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Mezeiova, Eva, Katarina Chalupova, Eugenie Nepovimova, Lukas Gorecki, Lukas Prchal, David Malinak, Kamil Kuca, Ondrej Soukup i Jan Korabecny. "Donepezil Derivatives Targeting Amyloid-β Cascade in Alzheimer's Disease". Current Alzheimer Research 16, nr 9 (29.10.2019): 772–800. http://dx.doi.org/10.2174/1567205016666190228122956.
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: Alzheimer's Disease (AD) is a neurodegenerative disorder with an increasing impact on society. Because currently available therapy has only a short-term effect, a huge number of novel compounds are developed every year exploiting knowledge of the various aspects of AD pathophysiology. To better address the pathological complexity of AD, one of the most extensively pursued strategies by medicinal chemists is based on Multi-target-directed Ligands (MTDLs). Donepezil is one of the currently approved drugs for AD therapy acting as an acetylcholinesterase inhibitor. In this review, we have made an extensive literature survey focusing on donepezil-derived MTDL hybrids primarily targeting on different levels cholinesterases and amyloid beta (Aβ) peptide. The targeting includes direct interaction of the compounds with Aβ, AChE-induced Aβ aggregation, inhibition of BACE-1 enzyme, and modulation of biometal balance thus impeding Aβ assembly.
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Meschaninova, Mariya I., Darya S. Novopashina, Olga A. Semikolenova, Vladimir N. Silnikov i Alya G. Venyaminova. "Novel Convenient Approach to the Solid-Phase Synthesis of Oligonucleotide Conjugates". Molecules 24, nr 23 (22.11.2019): 4266. http://dx.doi.org/10.3390/molecules24234266.
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A novel and convenient approach for the solid-phase 5′-functionalization of oligonucleotides is proposed in this article. The approach is based on the activation of free 5′-hydroxyl of polymer support-bound protected oligonucleotides by N,N′-disuccinimidyl carbonate followed by interaction with amino-containing ligands. Novel amino-containing derivatives of closo-dodecaborate, estrone, cholesterol, and α-tocopherol were specially prepared. A wide range of oligonucleotide conjugates bearing closo-dodecaborate, short peptide, pyrene, lipophilic residues (cholesterol, α-tocopherol, folate, estrone), aliphatic diamines, and propargylamine were synthesized and characterized to demonstrate the versatility of the approach. The developed method is suitable for the conjugate synthesis of oligonucleotides of different types (ribo-, deoxyribo-, 2′-O-methylribo-, and others).
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Ganesh, Shanmugam, i Rajadas Jayakumar. "Monolayer formation of short helical turn forming peptide derivatives at the air–water and air–solid interfaces". Chemical Physics Letters 380, nr 5-6 (październik 2003): 681–88. http://dx.doi.org/10.1016/j.cplett.2003.09.053.
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Niida, Ayumu, Yoko Kanematsu-Yamaki, Tomoko Asakawa, Yoshimasa Ishimura, Hisashi Fujita, Kouta Matsumiya, Naoki Nishizawa i in. "Antiobesity and emetic effects of a short-length peptide YY analog and its PEGylated and alkylated derivatives". Bioorganic & Medicinal Chemistry 26, nr 3 (luty 2018): 566–72. http://dx.doi.org/10.1016/j.bmc.2017.12.014.
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Wu, Xinghua, Yu Chen, Herve Aloysius i Longqin Hu. "A novel high-yield synthesis of aminoacyl p-nitroanilines and aminoacyl 7-amino-4-methylcoumarins: Important synthons for the synthesis of chromogenic/fluorogenic protease substrates". Beilstein Journal of Organic Chemistry 7 (27.07.2011): 1030–35. http://dx.doi.org/10.3762/bjoc.7.117.
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Aminoacyl p-nitroaniline (aminoacyl-pNA) and aminoacyl 7-amino-4-methylcoumarin (aminoacyl-AMC) are important synthons for the synthesis of chromogenic/fluorogenic protease substrates. A new efficient method was developed to synthesize aminoacyl-pNA and aminoacyl-AMC derivatives in excellent yields starting from either amino acids or their corresponding commercially available N-hydroxysuccinimide esters. The method involved the in situ formation of selenocarboxylate intermediate of protected amino acids and the subsequent non-nucleophilic amidation with an azide. Common protecting groups used in amino acid/peptide chemistry were all well-tolerated. The method was also successfully applied to the synthesis of a dipeptide conjugate, indicating that the methodology is applicable to the synthesis of chromogenic substrates containing short peptides. The method has general applicability to the synthesis of chromogenic and fluorogenic peptide substrates and represents a convenient and high-yield synthesis of N α-protected-aminoacyl-pNAs/AMCs, providing easy access to these important synthons for the construction of chromogenic/fluorogenic protease substrates through fragment condensation or stepwise elongation.