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822 KiB

Open AccessArticle

Bio-Inspired Nitrile Hydration by Peptidic Ligands Based on L-Cysteine, L-Methionine or L-Penicillamine and Pyridine-2,6-dicarboxylic Acid

by Cillian Byrne, Kate M. Houlihan, Prarthana Devi, Paul Jensen and Peter J. Rutledge

Molecules 2014, 19(12), 20751-20767; https://doi.org/10.3390/molecules191220751 - 12 Dec 2014

Cited by 8 | Viewed by 9302

Abstract

Nitrile hydratase (NHase, EC 4.2.1.84) is a metalloenzyme which catalyses the conversion of nitriles to amides. The high efficiency and broad substrate range of NHase have led to the successful application of this enzyme as a biocatalyst in the industrial syntheses of acrylamide [...] Read more.

Nitrile hydratase (NHase, EC 4.2.1.84) is a metalloenzyme which catalyses the conversion of nitriles to amides. The high efficiency and broad substrate range of NHase have led to the successful application of this enzyme as a biocatalyst in the industrial syntheses of acrylamide and nicotinamide and in the bioremediation of nitrile waste. Crystal structures of both cobalt(III)- and iron(III)-dependent NHases reveal an unusual metal binding motif made up from six sequential amino acids and comprising two amide nitrogens from the peptide backbone and three cysteine-derived sulfur ligands, each at a different oxidation state (thiolate, sulfenate and sulfinate). Based on the active site geometry revealed by these crystal structures, we have designed a series of small-molecule ligands which integrate essential features of the NHase metal binding motif into a readily accessible peptide environment. We report the synthesis of ligands based on a pyridine-2,6-dicarboxylic acid scaffold and L-cysteine, L-S-methylcysteine, L-methionine or L-penicillamine. These ligands have been combined with cobalt(III) and iron(III) and tested as catalysts for biomimetic nitrile hydration. The highest levels of activity are observed with the L-penicillamine ligand which, in combination with cobalt(III), converts acetonitrile to acetamide at 1.25 turnovers and benzonitrile to benzamide at 1.20 turnovers. Full article

(This article belongs to the Special Issue Peptide Chemistry)

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580 KiB

Open AccessArticle

Rational Design and Synthesis of Altered Peptide Ligands based on Human Myelin Oligodendrocyte Glycoprotein 35–55 Epitope: Inhibition of Chronic Experimental Autoimmune Encephalomyelitis in Mice

by Theodore Tselios, Mihalis Aggelidakis, Anthi Tapeinou, Vivian Tseveleki, Ioannis Kanistras, Dimitrios Gatos and John Matsoukas

Molecules 2014, 19(11), 17968-17984; https://doi.org/10.3390/molecules191117968 - 4 Nov 2014

Cited by 21 | Viewed by 7012

Abstract

Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease of the central nervous system and is an animal model of multiple sclerosis (MS). Although the etiology of MS remains unclear, there is evidence T-cell recognition of immunodominant epitopes of myelin proteins, such as the [...] Read more.

Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease of the central nervous system and is an animal model of multiple sclerosis (MS). Although the etiology of MS remains unclear, there is evidence T-cell recognition of immunodominant epitopes of myelin proteins, such as the 35–55 epitope of myelin oligodendrocyte glycoprotein (MOG), plays a pathogenic role in the induction of chronic EAE. Cyclization of peptides is of great interest since the limited stability of linear peptides restricts their potential use as therapeutic agents. Herein, we have designed and synthesized a number of linear and cyclic peptides by mutating crucial T cell receptor (TCR) contact residues of the human MOG_35–55 epitope. In particular, we have designed and synthesized cyclic altered peptide ligands (APLs) by mutating Arg⁴¹ with Ala or Arg⁴¹ and Arg⁴⁶ with Ala. The peptides were synthesized in solid phase on 2-chlorotrityl chloride resin (CLTR-Cl) using the Fmoc/t-Bu methodology. The purity of final products was verified by RP-HPLC and their identification was achieved by ESI-MS. It was found that the substitutions of Arg at positions 41 and 46 with Ala results in peptide analogues that reduce the severity of MOG-induced EAE clinical symptoms in C57BL/6 mice when co-administered with mouse MOG_35–55 peptide at the time of immunization. Full article

(This article belongs to the Special Issue Peptide Chemistry)

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398 KiB

Open AccessArticle

Poly(Ethylene Glycol)-Based Backbones with High Peptide Loading Capacities

by Aoife O'Connor, Jean-Noel Marsat, Annachiara Mitrugno, Tom Flahive, Niamh Moran, David Brayden and Marc Devocelle

Molecules 2014, 19(11), 17559-17577; https://doi.org/10.3390/molecules191117559 - 30 Oct 2014

Cited by 9 | Viewed by 11367

Abstract

Polymer-peptide conjugates are a promising class of compounds, where polymers can be used to overcome some of the limitations associated with peptides intended for therapeutic and/or diagnostic applications. Linear polymers such as poly(ethylene glycol) can be conjugated through terminal moieties and have therefore [...] Read more.

Polymer-peptide conjugates are a promising class of compounds, where polymers can be used to overcome some of the limitations associated with peptides intended for therapeutic and/or diagnostic applications. Linear polymers such as poly(ethylene glycol) can be conjugated through terminal moieties and have therefore limited loading capacities. In this research, functionalised linear poly(ethylene glycol)s are utilised for peptide conjugation, to increase their potential loading capacities. These poly(ethylene glycol) derivatives are conjugated to peptide sequences containing representative side-chain functionalised amino acids, using different conjugation chemistries, including copper-catalysed azide-alkyne cycloaddition, amide coupling and thiol-ene reactions. Conjugation of a sequence containing the RGD motif to poly(allyl glycidyl ether) by the thiol-ene reaction, provided a conjugate which could be used in platelet adhesion studies. Full article

(This article belongs to the Special Issue Peptide Chemistry)

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1182 KiB

Open AccessArticle

The Plant Decapeptide OSIP108 Can Alleviate Mitochondrial Dysfunction Induced by Cisplatin in Human Cells

by Pieter Spincemaille, Hamed Alborzinia, Jeroen Dekervel, Petra Windmolders, Jos Van Pelt, David Cassiman, Olivier Cheneval, David J. Craik, Julia Schur, Ingo Ott, Stefan Wölfl, Bruno P. A. Cammue and Karin Thevissen

Molecules 2014, 19(9), 15088-15102; https://doi.org/10.3390/molecules190915088 - 19 Sep 2014

Cited by 4 | Viewed by 6427

Abstract

We investigated the effect of the Arabidopsis thaliana-derived decapeptide OSIP108 on human cell tolerance to the chemotherapeutic agent cisplatin (Cp), which induces apoptosis and mitochondrial dysfunction. We found that OSIP108 increases the tolerance of HepG2 cells to Cp and prevents Cp-induced changes in [...] Read more.

We investigated the effect of the Arabidopsis thaliana-derived decapeptide OSIP108 on human cell tolerance to the chemotherapeutic agent cisplatin (Cp), which induces apoptosis and mitochondrial dysfunction. We found that OSIP108 increases the tolerance of HepG2 cells to Cp and prevents Cp-induced changes in basic cellular metabolism. More specifically, we demonstrate that OSIP108 reduces Cp-induced inhibition of respiration, decreases glycolysis and prevents Cp-uptake in HepG2 cells. Apart from its protective action against Cp in human cells, OSIP108 also increases the yeast Saccharomyces cerevisiae tolerance to Cp. A limited yeast-based study of OSIP108 analogs showed that cyclization does not severely affect its activity, which was further confirmed in HepG2 cells. Furthermore, the similarity in the activity of the D-stereoisomer (mirror image) form of OSIP108 with the L-stereoisomer suggests that its mode of action does not involve binding to a stereospecific receptor. In addition, as OSIP108 decreases Cp uptake in HepG2 cells and the anti-Cp activity of OSIP108 analogs without free cysteine is reduced, OSIP108 seems to protect against Cp-induced toxicity only partly via complexation. Taken together, our data indicate that OSIP108 and its cyclic derivatives can protect against Cp-induced toxicity and, thus, show potential as treatment options for mitochondrial dysfunction- and apoptosis-related conditions. Full article

(This article belongs to the Special Issue Peptide Chemistry)

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4099 KiB

Open AccessArticle

Peptides Derived from Rhopilema esculentum Hydrolysate Exhibit Angiotensin Converting Enzyme (ACE) Inhibitory and Antioxidant Abilities

by Jun Li, Qian Li, Jingyun Li and Bei Zhou

Molecules 2014, 19(9), 13587-13602; https://doi.org/10.3390/molecules190913587 - 2 Sep 2014

Cited by 28 | Viewed by 7610

Abstract

Jellyfish (Rhopilema esculentum) was hydrolyzed using alcalase, and two peptides with angiotensin-I-converting enzyme (ACE) inhibitory and antioxidant activities were purified by ultrafiltration and consecutive chromatographic methods. The amino acid sequences of the two peptides were identified as VKP (342 Da) and [...] Read more.

Jellyfish (Rhopilema esculentum) was hydrolyzed using alcalase, and two peptides with angiotensin-I-converting enzyme (ACE) inhibitory and antioxidant activities were purified by ultrafiltration and consecutive chromatographic methods. The amino acid sequences of the two peptides were identified as VKP (342 Da) and VKCFR (651 Da) by electrospray ionization tandem mass spectrometry. The IC₅₀ values of ACE inhibitory activities of the two peptides were 1.3 μM and 34.5 μM, respectively. Molecular docking results suggested that VKP and VKCFR bind to ACE through coordinating with the active site Zn(II) atom. Free radical scavenging activity and protection against hydrogen peroxide (H₂O₂)-induced rat cerebral microvascular endothelial cell (RCMEC) injury were used to evaluate the antioxidant activities of the two peptides. As the results clearly showed that the peptides increased the superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-px) activities in RCMEC cells), it is proposed that the R. esculentum peptides exert significant antioxidant effects. Full article

(This article belongs to the Special Issue Peptide Chemistry)

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2578 KiB

Open AccessArticle

Effects of Egg Yolk-Derived Peptide on Osteogenic Gene Expression and MAPK Activation

by Hye Kyung Kim, Myung-Gyou Kim and Kang-Hyun Leem

Molecules 2014, 19(9), 12909-12924; https://doi.org/10.3390/molecules190912909 - 25 Aug 2014

Cited by 21 | Viewed by 7852

Abstract

The present study investigated the effects of egg yolk-derived peptide (YPEP) on osteogenic activities and MAPK-regulation of osteogenic gene expressions. The effects of YPEP on cell proliferation, alkaline phosphatase activity, collagen synthesis, and mineralization were measured in human osteoblastic MG-63 cells. Activation of [...] Read more.

The present study investigated the effects of egg yolk-derived peptide (YPEP) on osteogenic activities and MAPK-regulation of osteogenic gene expressions. The effects of YPEP on cell proliferation, alkaline phosphatase activity, collagen synthesis, and mineralization were measured in human osteoblastic MG-63 cells. Activation of MAPKs and downstream transcription factors such as extracellular-signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase 1/2 (JNK1/2), p38, ELK1, and cJUN were examined using western blot analysis. YPEP dose-dependently increased MG-63 cell proliferation, ALP activity, collagen synthesis, and calcium deposition. YPEP activated ERK1/2, p38, and ELK1 phosphorylation whereas JNK and cJUN were not affected by YPEP. The COL1A1 (collagen, type I, alpha 1), ALPL (alkaline phosphatase), and SPP1 (secreted phosphoprotein 1, osteopontin) gene expressions were increased while BGLAP (osteocalcin) was not affected by YPEP. The ERK1/2 inhibitor (PD98509) blocked the YPEP-induced COL1A1 and ALPL gene expressions as well as ELK1 phosphorylation. The p38 inhibitor (SB203580) blocked YPEP-induced COL1A1 and ALPL gene expressions. SPP1 gene expression was not affected by these MAPK inhibitors. In conclusion, YPEP treatment stimulates the osteogenic differentiation via the MAPK/ELK1 signaling pathway. These results could provide a mechanistic explanation for the bone-strengthening effects of YPEP. Full article

(This article belongs to the Special Issue Peptide Chemistry)

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1778 KiB

Open AccessArticle

Tryptophan as a Probe to Study the Anticancer Mechanism of Action and Specificity of α-Helical Anticancer Peptides

by Guirong Li, Yibing Huang, Qi Feng and Yuxin Chen

Molecules 2014, 19(8), 12224-12241; https://doi.org/10.3390/molecules190812224 - 13 Aug 2014

Cited by 28 | Viewed by 7111

Abstract

In the present study, a single tryptophan, as a fluorescence probe, was shifted from the N-terminus to the middle and to the C-terminus of a 26-residue α-helical anticancer peptide sequence to study the mechanism of action and specificity. The hydrophobicity of peptides, as [...] Read more.

In the present study, a single tryptophan, as a fluorescence probe, was shifted from the N-terminus to the middle and to the C-terminus of a 26-residue α-helical anticancer peptide sequence to study the mechanism of action and specificity. The hydrophobicity of peptides, as well as peptide helicity and self-associating ability, were slightly influenced by the position change of tryptophan in the peptide sequence, while the hemolytic activity and anticancer activity of the peptide analogs remained the same. The tryptophan fluorescence experiment demonstrated that peptide analogs were more selective against LUVs mimicking cancer cell membranes than LUVs mimicking normal cell membranes. During the interaction with target membranes, the N-terminus of an anticancer peptide may be inserted vertically or tilted into the hydrophobic components of the phospholipid bilayer first. The thermodynamic parameters of the peptides PNW and PCW, when interacting with zwitterionic DMPC or negatively charged DMPS, were determined by ITC. DSC experiments showed that peptide analogs significantly altered the phase transition profiles of DMPC, but did not dramatically modify the phase transition of DMPS. It is demonstrated that hydrophobic interactions are the main driving force for peptides interacting with normal cell membranes, whilst, electrostatic interactions dominate the interactions between peptides and cancer cell membranes. Utilizing tryptophan as a fluorescence probe molecule appears to be a practicable approach to determine the interaction of peptides with phospholipid bilayers. Full article

(This article belongs to the Special Issue Peptide Chemistry)

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818 KiB

Open AccessArticle

Effects of Single Amino Acid Substitution on the Biophysical Properties and Biological Activities of an Amphipathic α-Helical Antibacterial Peptide Against Gram-Negative Bacteria

by Juanjuan Tan, Jinfeng Huang, Yibing Huang and Yuxin Chen

Molecules 2014, 19(8), 10803-10817; https://doi.org/10.3390/molecules190810803 - 24 Jul 2014

Cited by 18 | Viewed by 7610

Abstract

An antimicrobial peptide, known as V13K, was utilized as the framework to study the effects of charge, hydrophobicity and helicity on the biophysical properties and biological activities of α-helical peptides. Six amino acids (Lys, Glu, Gly, Ser, Ala, and Leu) were individually used [...] Read more.

An antimicrobial peptide, known as V13K, was utilized as the framework to study the effects of charge, hydrophobicity and helicity on the biophysical properties and biological activities of α-helical peptides. Six amino acids (Lys, Glu, Gly, Ser, Ala, and Leu) were individually used to substitute the original hydrophobic valine at the selected sixteenth location on the non-polar face of V13K. The results showed that the single amino acid substitutions changed the hydrophobicity of peptide analogs as monitored by RP-HPLC, but did not cause significant changes on peptide secondary structures both in a benign buffer and in a hydrophobic environment. The biological activities of the analogs exhibited a hydrophobicity-dependent behavior. The mechanism of peptide interaction with the outer membrane and cytoplasmic membrane of Gram-negative bacteria was investigated. We demonstrated that this single amino acid substitution method has valuable potential for the rational design of antimicrobial peptides with enhanced activities. Full article

(This article belongs to the Special Issue Peptide Chemistry)

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560 KiB

Open AccessArticle

The Effect of Mini-PEG-Based Spacer Length on Binding and Pharmacokinetic Properties of a ⁶⁸Ga-Labeled NOTA-Conjugated Antagonistic Analog of Bombesin

by Zohreh Varasteh, Ulrika Rosenström, Irina Velikyan, Bogdan Mitran, Mohamed Altai, Hadis Honarvar, Maria Rosestedt, Gunnar Lindeberg, Jens Sörensen, Mats Larhed, Vladimir Tolmachev and Anna Orlova

Molecules 2014, 19(7), 10455-10472; https://doi.org/10.3390/molecules190710455 - 17 Jul 2014

Cited by 63 | Viewed by 9894

Abstract

The overexpression of gastrin-releasing peptide receptor (GRPR) in cancer can be used for peptide-receptor mediated radionuclide imaging and therapy. We have previously shown that an antagonist analog of bombesin RM26 conjugated to 1,4,7-triazacyclononane-N,N',N''-triacetic acid (NOTA) via a [...] Read more.

The overexpression of gastrin-releasing peptide receptor (GRPR) in cancer can be used for peptide-receptor mediated radionuclide imaging and therapy. We have previously shown that an antagonist analog of bombesin RM26 conjugated to 1,4,7-triazacyclononane-N,N',N''-triacetic acid (NOTA) via a diethyleneglycol (PEG₂) spacer (NOTA-PEG₂-RM26) and labeled with ⁶⁸Ga can be used for imaging of GRPR-expressing tumors. In this study, we evaluated if a variation of mini-PEG spacer length can be used for optimization of targeting properties of the NOTA-conjugated RM26. A series of analogs with different PEG-length (n = 2, 3, 4, 6) was synthesized, radiolabeled and evaluated in vitro and in vivo. The IC₅₀ values of ^natGa-NOTA-PEG_n-RM26 (n = 2, 3, 4, 6) were 3.1 ± 0.2, 3.9 ± 0.3, 5.4 ± 0.4 and 5.8 ± 0.3 nM, respectively. In normal mice all conjugates demonstrated similar biodistribution pattern, however ⁶⁸Ga-NOTA-PEG₃-RM26 showed lower liver uptake. Biodistribution of ⁶⁸Ga-NOTA-PEG₃-RM26 was evaluated in nude mice bearing PC-3 (prostate cancer) and BT-474 (breast cancer) xenografts. High uptake in tumors (4.6 ± 0.6%ID/g and 2.8 ± 0.4%ID/g for PC-3 and BT-474 xenografts, respectively) and high tumor-to-background ratios (tumor/blood of 44 ± 12 and 42 ± 5 for PC-3 and BT-474 xenografts, respectively) were found already at 2 h p.i. of ⁶⁸Ga-NOTA-PEG₃-RM26. Results of this study suggest that variation in the length of the PEG spacer can be used for optimization of targeting properties of peptide-chelator conjugates. However, the influence of the mini-PEG length on biodistribution is minor when di-, tri-, tetra- and hexaethylene glycol are compared. Full article

(This article belongs to the Special Issue Peptide Chemistry)

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5317 KiB

Open AccessCommunication

Mechanistic Insight into CM₁₈-Tat₁₁ Peptide Membrane-Perturbing Action by Whole-Cell Patch-Clamp Recording

by Anna Fasoli, Fabrizio Salomone, Mascia Benedusi, Claudia Boccardi, Giorgio Rispoli, Fabio Beltram and Francesco Cardarelli

Molecules 2014, 19(7), 9228-9239; https://doi.org/10.3390/molecules19079228 - 2 Jul 2014

Cited by 13 | Viewed by 7771

Abstract

The membrane-destabilization properties of the recently-introduced endosomolytic CM₁₈-Tat₁₁ hybrid peptide (KWKLFKKIGAVLKVLTTG-YGRKKRRQRRR, residues 1–7 of cecropin-A, 2–12 of melittin, and 47–57 of HIV-1 Tat protein) are investigated in CHO-K1 cells by using the whole-cell configuration of the patch-clamp technique. CM₁₈ [...] Read more.

The membrane-destabilization properties of the recently-introduced endosomolytic CM₁₈-Tat₁₁ hybrid peptide (KWKLFKKIGAVLKVLTTG-YGRKKRRQRRR, residues 1–7 of cecropin-A, 2–12 of melittin, and 47–57 of HIV-1 Tat protein) are investigated in CHO-K1 cells by using the whole-cell configuration of the patch-clamp technique. CM₁₈-Tat₁₁, CM₁₈, and Tat₁₁ peptides are administered to the cell membrane with a computer-controlled micro-perfusion system. CM₁₈-Tat₁₁ induces irreversible cell-membrane permeabilization at concentrations (≥4 µM) at which CM₁₈ triggers transient pore formation, and Tat₁₁ does not affect membrane integrity. We argue that the addition of the Tat₁₁ module to CM₁₈ is able to trigger a shift in the mechanism of membrane destabilization from “toroidal” to “carpet”, promoting a detergent-like membrane disruption. Collectively, these results rationalize previous observations on CM₁₈-Tat₁₁ delivery properties that we believe can guide the engineering of new modular peptides tailored to specific cargo-delivery applications. Full article

(This article belongs to the Special Issue Peptide Chemistry)

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1315 KiB

Open AccessArticle

A Novel Phage-Library-Selected Peptide Inhibits Human TNF-α Binding to Its Receptors

by Jlenia Brunetti, Barbara Lelli, Silvia Scali, Chiara Falciani, Luisa Bracci and Alessandro Pini

Molecules 2014, 19(6), 7255-7268; https://doi.org/10.3390/molecules19067255 - 3 Jun 2014

Cited by 8 | Viewed by 7561

Abstract

We report the identification of a new human tumor necrosis factor-alpha (TNF-α) specific peptide selected by competitive panning of a phage library. Competitive elution of phages was obtained using the monoclonal antibody adalimumab, which neutralizes pro-inflammatory processes caused by over-production of TNF-α in [...] Read more.

We report the identification of a new human tumor necrosis factor-alpha (TNF-α) specific peptide selected by competitive panning of a phage library. Competitive elution of phages was obtained using the monoclonal antibody adalimumab, which neutralizes pro-inflammatory processes caused by over-production of TNF-α in vivo, and is used to treat severe symptoms of rheumatoid arthritis. The selected peptide was synthesized in monomeric and branched form and analyzed for binding to TNF-α and competition with adalimumab and TNF-α receptors. Results of competition with TNF-α receptors in surface plasmon resonance and melanoma cells expressing both TNF receptors make the peptide a candidate compound for the development of a novel anti-TNF-α drug. Full article

(This article belongs to the Special Issue Peptide Chemistry)

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Review

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1393 KiB

Open AccessReview

¹⁸F-Labeled Peptides: The Future Is Bright

by Susan Richter and Frank Wuest

Molecules 2014, 19(12), 20536-20556; https://doi.org/10.3390/molecules191220536 - 8 Dec 2014

Cited by 117 | Viewed by 13750

Abstract

Radiolabeled peptides have been the subject of intense research efforts for targeted diagnostic imaging and radiotherapy over the last 20 years. Peptides offer several advantages for receptor imaging and targeted radiotherapy. The low molecular weight of peptides allows for rapid clearance from the [...] Read more.

Radiolabeled peptides have been the subject of intense research efforts for targeted diagnostic imaging and radiotherapy over the last 20 years. Peptides offer several advantages for receptor imaging and targeted radiotherapy. The low molecular weight of peptides allows for rapid clearance from the blood and non-target tissue, which results in favorable target-to-non-target ratios. Moreover, peptides usually display good tissue penetration and they are generally non-immunogenic. A major drawback is their potential low metabolic stability. The majority of currently used radiolabeled peptides for targeted molecular imaging and therapy of cancer is labeled with various radiometals like ^99mTc, ⁶⁸Ga, and ¹⁷⁷Lu. However, over the last decade an increasing number of ¹⁸F-labeled peptides have been reported. Despite of obvious advantages of ¹⁸F like its ease of production in large quantities at high specific activity, the low β⁺ energy (0.64 MeV) and the favorable half-life (109.8 min), ¹⁸F-labeling of peptides remains a special challenge. The first part of this review will provide a brief overview on chemical strategies for peptide labeling with ¹⁸F. A second part will discuss recent technological advances for ¹⁸F-labeling of peptides with special focus on microfluidic technology, automation, and kit-like preparation of ¹⁸F-labeled peptides. Full article

(This article belongs to the Special Issue Peptide Chemistry)

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839 KiB

Open AccessReview

Native Chemical Ligation: A Boon to Peptide Chemistry

by Parashar Thapa, Rui-Yang Zhang, Vinay Menon and Jon-Paul Bingham

Molecules 2014, 19(9), 14461-14483; https://doi.org/10.3390/molecules190914461 - 12 Sep 2014

Cited by 60 | Viewed by 12185

Abstract

The use of chemical ligation within the realm of peptide chemistry has opened various opportunities to expand the applications of peptides/proteins in biological sciences. Expansion and refinement of ligation chemistry has made it possible for the entry of peptides into the world of [...] Read more.

The use of chemical ligation within the realm of peptide chemistry has opened various opportunities to expand the applications of peptides/proteins in biological sciences. Expansion and refinement of ligation chemistry has made it possible for the entry of peptides into the world of viable oral therapeutic drugs through peptide backbone cyclization. This progression has been a journey of chemical exploration and transition, leading to the dominance of native chemical ligation in the present advances of peptide/protein applications. Here we illustrate and explore the historical and current nature of peptide ligation, providing a clear indication to the possibilities and use of these novel methods to take peptides outside their typically defined boundaries. Full article

(This article belongs to the Special Issue Peptide Chemistry)

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Open AccessReview

Recent Advances in Chemoenzymatic Peptide Syntheses

by Kenjiro Yazawa and Keiji Numata

Molecules 2014, 19(9), 13755-13774; https://doi.org/10.3390/molecules190913755 - 3 Sep 2014

Cited by 86 | Viewed by 11387

Abstract

Chemoenzymatic peptide synthesis is the hydrolase-catalyzed stereoselective formation of peptide bonds. It is a clean and mild procedure, unlike conventional chemical synthesis, which involves complicated and laborious protection-deprotection procedures and harsh reaction conditions. The chemoenzymatic approach has been utilized for several decades because [...] Read more.

Chemoenzymatic peptide synthesis is the hydrolase-catalyzed stereoselective formation of peptide bonds. It is a clean and mild procedure, unlike conventional chemical synthesis, which involves complicated and laborious protection-deprotection procedures and harsh reaction conditions. The chemoenzymatic approach has been utilized for several decades because determining the optimal conditions for conventional synthesis is often time-consuming. The synthesis of poly- and oligopeptides comprising various amino acids longer than a dipeptide continues to pose a challenge owing to the lack of knowledge about enzymatic mechanisms and owing to difficulty in optimizing the pH, temperature, and other reaction conditions. These drawbacks limit the applications of the chemoenzymatic approach. Recently, a variety of enzymes and substrates produced using recombinant techniques, substrate mimetics, and optimal reaction conditions (e.g., frozen aqueous media and ionic liquids) have broadened the scope of chemoenzymatic peptide syntheses. In this review, we highlight the recent advances in the chemoenzymatic syntheses of various peptides and their use in developing new materials and biomedical applications. Full article

(This article belongs to the Special Issue Peptide Chemistry)

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1766 KiB

Open AccessReview

Cyclodepsipeptides: A Rich Source of Biologically Active Compounds for Drug Research

by Sivatharushan Sivanathan and Jürgen Scherkenbeck

Molecules 2014, 19(8), 12368-12420; https://doi.org/10.3390/molecules190812368 - 15 Aug 2014

Cited by 82 | Viewed by 12229

Abstract

Faced with the need to find new drugs for all kinds of diseases, science sees that Nature offers numerous classes of compounds showing an impressively high biological potential. Among those are the cyclodepsipeptides, hybrid structures composed of amino and hydroxy acids. In the [...] Read more.

Faced with the need to find new drugs for all kinds of diseases, science sees that Nature offers numerous classes of compounds showing an impressively high biological potential. Among those are the cyclodepsipeptides, hybrid structures composed of amino and hydroxy acids. In the past decades numerous cyclodepsipeptides have been isolated and their potential as drugs has been studied extensively. For several cyclodepsipeptides total syntheses both in solution and on solid-phase have been established, allowing the production of combinatorial libraries. In addition, the biosynthesis of specific cyclodepsipeptides has been elucidated and used for the chemoenzymatic preparation of nonnatural analogues. This review summarizes the recent literature on cyclic tetra- to decadepsipeptides, composed exclusively of α-amino- and α-hydroxy acids. Full article

(This article belongs to the Special Issue Peptide Chemistry)

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1796 KiB

Open AccessReview

Antifungal Plant Defensins: Mechanisms of Action and Production

by Kim Vriens, Bruno P. A. Cammue and Karin Thevissen

Molecules 2014, 19(8), 12280-12303; https://doi.org/10.3390/molecules190812280 - 14 Aug 2014

Cited by 196 | Viewed by 15861

Abstract

Plant defensins are small, cysteine-rich peptides that possess biological activity towards a broad range of organisms. Their activity is primarily directed against fungi, but bactericidal and insecticidal actions have also been reported. The mode of action of various antifungal plant defensins has been [...] Read more.

Plant defensins are small, cysteine-rich peptides that possess biological activity towards a broad range of organisms. Their activity is primarily directed against fungi, but bactericidal and insecticidal actions have also been reported. The mode of action of various antifungal plant defensins has been studied extensively during the last decades and several of their fungal targets have been identified to date. This review summarizes the mechanism of action of well-characterized antifungal plant defensins, including RsAFP2, MsDef1, MtDef4, NaD1 and Psd1, and points out the variety by which antifungal plant defensins affect microbial cell viability. Furthermore, this review summarizes production routes for plant defensins, either via heterologous expression or chemical synthesis. As plant defensins are generally considered non-toxic for plant and mammalian cells, they are regarded as attractive candidates for further development into novel antimicrobial agents. Full article

(This article belongs to the Special Issue Peptide Chemistry)

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