Linear Oligopeptides Research Articles

A comprehensive review of chemistry and pharmacological aspects of natural cyanobacterial azoline-based circular and linear oligopeptides

The cyanobacterial oligopeptides are recognized for being highly selective, efficacious and relatively safer compounds with diverse bioactivities. Azoline-based natural compounds consist of heterocycles which are reduced analogues of five-membered heterocyclic azoles. Among other varieties of azoline-based natural compounds, the heteropeptides bearing oxazoline or thiazoline heterocycles possess intrinsic structural properties with captivating pharmacological profiles, representing excellent templates for the design of novel therapeutics. The specificity of heteropeptides has been translated into prominent safety, tolerability, and efficacy profiles in humans. These peptidic congeners serve as ideal intermediary between small molecules and biopharmaceuticals based on their typically low production complexity compared to the protein-based biopharmaceuticals. The distinct bioproperties and unique structures render these heteropeptides one of the most promising lead compounds for drug discovery. The high degree of chemical diversity in cyanobacterial secondary metabolites may constitute a prolific source of new entities leading to the development of new pharmaceuticals. This review focuses on the azoline-based natural oligopeptides with emphasis on distinctive structural features, stereochemical aspects, biological activities, structure activity relationship, synthetic and biosynthetic aspects as well as mode of action of cyanobacteria-derived peptides.

Electric field controlled uphill electron migration along α-helical oligopeptides.

A systematic study on applied electric field effects (Eapp) on electron transfer along the peptides is very important for the regulation of electron transfer behaviors so as to realize the functions of proteins. In this work, we computationally investigated the uphill migration behaviors of excess electrons along the peptide chains under Eapp using the density functional theory method. We examined the electronic property changes of the model α-helical oligopeptides, the dynamics behavior of an excess electron along the peptide chains under Eapp opposite to the internal dipole field of peptides. We found that Eapp of different intensities can effectively modulate the electron-binding abilities, Frontier molecular orbital (FMO) energies and distributions, dipole moments and other corresponding properties with different degrees. The electron-binding abilities of α-helical oligopeptides revealed by vertical electron affinity and FMO energies decrease in weak Eapp and then increase greatly in high Eapp, while the dipole moments change mildly in weak Eapp and increase significantly until a threshold and then become gentle in high Eapp. Analysis of FMO and electron distributions indicates that an excess electron can migrate uphill from the N-terminus to the C-terminus of the α-helical peptides in an irregular jump mode as Eapp linearly increases. Another interesting finding is that α-helical peptides with diverse chain lengths have different sensitivities to Eapp. The longer the peptide is, the more obvious the effects of Eapp are. Additionally, compared to the Eapp effect on linear oligopeptides, we summarized the systematic rule about the Eapp effect on excess electron migration uphill along the peptide chains. Clearly, this work not only enriches the information of the Eapp effect on electronic properties and electron transfers in the helical peptides, but also provides a new perspective for modulating electron migration behaviors in protein electronics engineering.

Water-Mediated Peptide Bond Formation in the Gas Phase: A Model Prebiotic Reaction.

The emergence of life on the prebiotic Earth must have involved the formation of polypeptides, yet the polymerization of amino acids is thermodynamically unfavorable under biologically relevant aqueous conditions because amino acids are zwitterions in solution and because of the production of a water molecule through a condensation reaction. Many mechanisms for overcoming this thermodynamic unfavorability have been proposed, but the role of gas phase water clusters has not been investigated. We present the thermodynamics of the water-mediated gas phase dimerization reaction of glycine as a model for the atmospheric polymerization of amino acids prior to the emergence of biological machinery. We hypothesize that atmospheric aerosols may have played a major role in the prebiotic formation of peptide bonds by providing the thermodynamic driving force to facilitate increasingly stable linear oligopeptides. In addition, we hypothesize that small aerosols orient amino acids on their surfaces, thus providing the correct molecular orientations to funnel the reaction pathways of peptides through transition states that lead eventually to polypeptide products. Using density functional theory and a thorough configurational sampling technique, we show that the thermodynamic spontaneity of the linear dimerization of glycine in the gas phase can be driven by the addition of individual water molecules.

Nonlinear Migration Dynamics of Excess Electrons along Linear Oligopeptides Controlled by an Applied Electric Field.

Migration of an excess electron along linear oligopeptides governed by the external electric field (Eex ) which is against the inner dipole electric field is theoretically investigated, including the effects of Eex on the structural and electronic properties of electron migration. Two structural properties including electron-binding ability and the dipole moment of linear oligopeptides are sensitive to the Eex values and can be largely modulated by Eex due to the competition of Eex and the inner electric field and electron transfer caused by Eex . In the case of low Eex values, two structural properties decrease slightly, while for high Eex values, the electron-binding ability continually increases strongly, with dipole moments firstly increasing significantly and then increasing more slowly at higher Eex . Additionally, linear oligopeptides of different chain lengths influence the modulation extent of Eex and the longer the chain length is, the more sensitive modulation of Eex is. In addition, electronic properties represented by electron spin densities and singly occupied molecular orbital distributions vary with Eex intensities, leading to an unusual electron migration behavior. As Eex increases, an excess electron transfers from the N-terminus to the C-terminus and jumps over a neighboring dipole unit of two termini to other units, respectively, instead of transferring by means of a one-by-one dipole unit hopping mechanism. These findings not only promote a deeper understanding of the connection between Eex and structural and electronic properties of electron transfer behavior in peptides, but also provide a new insight into the modulation of electron migration along the oligopeptides.

One Step up the Ladder of Prebiotic Complexity: Formation of Nonrandom Linear Polypeptides from Binary Systems of Amino Acids on Silica.

Evidence for the formation of linear oligopeptides with nonrandom sequences from mixtures of amino acids coadsorbed on silica and submitted to a simple thermal activation is presented. The amino acid couples (glutamic acid+leucine) and (aspartic acid+valine) were deposited on a fumed silica and submitted to a single heating step at moderate temperature. The evolution of the systems was characterized by X-ray diffraction, infrared spectroscopy, thermosgravimetric analysis, HPLC, and electrospray ionization mass spectrometry (ESI-MS). Evidence for the formation of amide bonds was found in all systems studied. While the products of single amino acids activation on silica could be considered as evolutionary dead ends, (glutamic acid+leucine) and, at to some extent, (aspartic acid+valine) gave rise to the high yield formation of linear peptides up to the hexamers. Oligopeptides of such length have not been observed before in surface polymerization scenarios (unless the amino acids had been deposited by chemical vapor deposition, which is not realistic in a prebiotic environment). Furthermore, not all possible amino acid sequences were present in the activation products, which is indicative of polymerization selectivity. These results are promising for origins of life studies because they suggest the emergence of nonrandom biopolymers in a simple prebiotic scenario.

Tug-of-War in a Dynamic Helical Peptide: Solvent-Induced Helix-Helix Transition of a Lactam-Bridged Peptide Composed of Point- and Axial Chiralities Remote from Each Other.

The dynamic axial chirality of oligopeptide-bound 2,2'-bipyridine (bpy) residues can be remote-controlled and diastereoselectively locked. A right-handed (P)-310 -helix is first induced in the dynamic helical oligopeptide by an l-valine (l-Val) far from the bpy moiety and the induced axial bpy chirality is diastereoselectively dioxidized. The resulting l-Val-containing linear oligopeptides at the 3,3'-positions retain their (P)-310 -helices independent of the axial chirality (aR or aS) of the N-terminal N,N'-dioxide-bpy unit, while a lactam-bridged dynamic helical oligopeptide exhibits a unique solvent-induced helix-helix transition as a result of competitive helix-inducing biases between the l-Val and (aR) or (aS)-N,N'-dioxide-bpy residues remote from each other along the entire oligopeptide chain in a tug-of-war like manner.

Bioinspired Nanotubes from Self‐Assembly of a Linear l,d‐Oligopeptide‐Poly(ethylene glycol) Conjugate

The preparation and structural organization of a new bioinspired nanomaterial are investigated. A hybrid conjugate is obtained by end‐linking a linear octapeptide with regular alternating enantiomeric sequence to poly(ethylene glycol). This conjugate is able to self‐assemble, forming well‐defined nanorods having core/shell morphology with an internal peptide single channel that has, for the first time, been clearly visualized by transmission electron microscopy (TEM) images. It is remarkable that well‐defined cylindrical nanoparticles can be formed starting from a linear oligopeptide, the synthesis of which is significantly easier than that of the homologous cycles. In addition, the synthetic strategy and the structure of the conjugate ensure a controlled and regular pegylation of the aggregates and high density PEG blocks in the corona, making the nanoparticles more resistant to phagocytosis and able to prevent biofouling. Such features, along with biocompatibility and stability, make these nanoparticles promising candidates for drug delivery. image

Stability of some microginins synthesized by the cyanobacterium Woronichinia naegeliana (Unger) Elenkin

SummaryMicroginins are linear oligopeptides synthesized by cyanobacteria. The literature data on their characteristics are scant. This study examined the influence of abiotic factors including pH, temperature, visible and ultraviolet radiation on the stability of the microginins FR3 (MG‐FR3), FR4 (MG‐FR4) and 757 (MG‐757) synthesized by Woronichinia naegeliana. In alkaline conditions (pH 9) only the concentration of MG‐757 was reduced significantly, by 14.3%. The tested microginins were stable at room temperature (half‐life 7–17 weeks). Boiling for one hour caused 26.1% decomposition of MG‐FR4 and 26.8% decomposition of MG‐757; MG‐FR3 was not significantly affected. Under visible radiation the initial content of MG‐FR4 declined 23.0%, but MG‐FR3 and MG‐757 proved insensitive to it. Treatment with a high dose of UV radiation (36 μmol m−2 s−1) caused the tested microginins to degrade by 13.8% to 21.4%. The study showed these microginins to be oligopeptides of high stability, the most stable of them being MG‐FR3.

Enhancement of the helical content and stability induced in a linear oligopeptide by ani, i+4 intramolecularly double stapled, overlapping, bicyclic [31, 22, 5]-(E)ene motif

Two consecutive i, i+4 intramolecular, side chain-to-side chain, macrocyclizations of different type carried out on a preformed, partially helical peptide result in a largely predominant, double stapled, overlapping, bicyclic [31,22,5]-(E)ene motif. A detailed ECD and NMR conformational study revealed a significant enhancement of the original helical content and stability, accompanied by an increase of the α-helix amount over that of the 3(10)-helix.

Theory study on glycine linear oligopeptide vibrational spectrum frequency shift

By using the density functional theory, glycine linear oligopeptide of different lengths was geometrically optimized on the 6-31G (d) basis set level, their growth processes were simulated, and the average binding energy and vibration frequency were calculated with geometry. The results showed that the average binding energies tend to change in a regular pattern and stabilize with the number of residues increasing; With the oligopeptide chain bond length analysis it was found that the chain to the radial direction there is a opposite trend for chain and radial direction, which is anisotropic. It was found by the IR spectrum analysis that red shifts and blue shifts occur respectively when the same group of peptide bond vibrate, which is anisotropic; These phenomena originate from that quasi one-dimensional nanostructures lead to the anisotropy of the bond length; the induced effects, coupling effects and hydrogen bonding etc. between the same groups lead to the vibration frequency red shifts and blue shifts. The authors conclude that the growth of glycine linear oligopeptide is conducive to stability of the structure, and the authors infer that the oligopeptide has the tendency of self-assembled growth; Through the conformation and spectrum, the authors infer that there is a size effect in physical and chemical properties. The physical and chemical properties of peptide chain end group are extremely stable and unaffected by the impact of the oligopeptide chain length The results are significant to measuring the length and the number of residue of peptide, and to manufacturing the special features oligopeptide chain.

Highly Constrained Linear Oligopeptides Containing Heterocyclic α‐Amino Carboxylic Acids

AbstractTwo spiroheterocyclic 2H‐azirin‐3‐amines, 1f and 1g, were shown to be useful synthons for the dipeptides N‐(4‐aminotetrahydro‐2H‐pyran‐4‐yl)prolinate (Thp‐Pro) and the corresponding thiopyran derivative, Tht‐Pro, respectively. By coupling of 4‐bromobenzoic acid with 1f or 1g and saponification, followed by repeating the coupling and saponification steps, oligopeptides of type 4‐BrBz‐(Thp‐Pro)n‐OMe and 4‐BrBz‐(Tht‐Pro)n‐OMe were prepared, and their conformations were evaluated in solution by NMR techniques and in the crystalline state by X‐ray crystallography. All of these sterically highly congested oligopeptides adopt fairly rigid helical conformations. It is interesting to note that the hexapeptide with Thp forms a 310‐helix, whereas the Tht analog has a β‐bend ribbon spiral confirmation.

Abstract A116: Stable and efficient delivery of docetaxel by micelle encapsulation using a tripodal cyclotriphosphazene amphiphile.

Abstract Docetaxel, a semi-synthetic analogue of paclitaxel, is currently one of the most important chemotherapeutic agents, since it is clinically very efficacious against a variety of tumors. Docetaxel is known to be more potent than paclitaxel, but its photo-instability causes more inconveniences in drug storage and patient treatment compared with paclitaxel. Docetaxel is solubilized in aqueous solution by formulation using a surfactant polysorbate 80 (Tween 80). Docetaxel in such a formulation named Taxotere is known to cause several adverse effects. Therefore, a great deal of efforts has been devoted to replace the surfactant polysorbate 80 with polymeric micelles composed of linear amphiphilic block copolymers. However, most of the linear block copolymers exposed commonly a few critical problems for practical application, and in particular, docetaxel-loaded polymeric micelles are not stable enough to hold the drug component in the micelle core and drug precipitates mostly within 24 h after drug loading. We have recently developed a novel class of cyclotriphosphazene micelles of a general formula [N=P(X)(Y)]3 prepared by stepwise substitutions of cyclic chlorophosphazene [N=PCl2]3 with equimolar hydrophilic (X) and hydrophobic (Y) nucleophiles in cis-nongeminal way. In particular, the tripodal amphiphiles with a methoxy poly(ethylene glycol) as a hydrophilic group and a linear oligopeptide as a hydrophobic group have been found to self-assemble into very stable spherical micelles with a mean diameter less than 10 nm and a CMC value of 5 mg/L in aqueous solution. Docetaxel micelle-encapsulated by a tripodal amphiphilile [NP(PEG750)(GlyPheLeu)2Et]3 (CP750) exhibited outstanding drug-loaded micelle stability in aqueous solution compared with the polymeric micelles assembled from linear block copolymers. Furthermore, docetaxel micelle-encapsulated by CP750 is obtainable in solvent free powder form, which is immediately soluble in any aqueous media including saline and PBS and very stable to photo-degradation even in the room light at room temperature. Docetaxel micelle-encapsulated by CP750 displayed significantly improved pharmacokinetic profile compared with Taxotere currently in clinical use. Furthermore, its in vivo xenograft trials exhibited outstanding antitumor efficacy by showing complete tumor regression against the breast cancer cells (MDA-MB-231) at a low dose of 5 mg/kg, which is only 1/3 of the optimum dose of Taxotere. Furthermore, according to the acute toxicity study, docetaxel micelle-encapsulated by CP750 exhibited a much higher LD50 value of 75 mg/kg compared with 28 mg/kg of docetaxel in Taxotere. Thus docetaxel micelle-encapsulated by CP750 has entered the stage of preclinical studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A116.

Amphiphilic Cyclotriphosphazenes Grafted with Branched Oligopeptides

Branched oligopeptides prepared by coupling a very hydrophobic aspartic diamino acid ethyl ester such as Asp <TEX>$(LeuEt)_2$</TEX>, <TEX>$Asp(IleEt)_2$</TEX> and <TEX>$Asp(PheEt)_2$</TEX> to glycine or glycylphenylalanine were grafted to the cyclotriphosphazene backbone bearing an equimolar hydrophilic poly(ethylene glycol) (PEG). The properties of the resultant amphiphiles were examined in comparison with those of the linear oligopeptide analogues previously reported. All cyclic phosphazene trimers grafted with the branched tetra- and pentapeptides displayed a normal trend of thermosensitivity depending on their hydrophilic to hydrophobic balance, but the stability and particle size of their micelles were found to be greatly dependent on the fine structure of the branched oligopeptides grafted. The trimers bearing branched tetrapeptides with a low hydrophobicity were found to form unstable micelles initially, which reassemble into thermodynamically more stable polymersomes.

Liquid crystals decorated with linear oligopeptide FLAG for applications in immunobiosensors

Immunobiosensors are emerging as powerful tools for diagnostic applications. In this paper, we exploit optical properties of liquid crystal (LC) and the specific epitope–antibody interaction to develop an optical immunobiosensor which can be used to detect monoclonal anti-FLAG M2, a model antibody. The sensitive layer of this immunobiosensor is a monolayer of immobilized oligopeptide CDYKDDDDK (FLAG) at an LC/aqueous interface. The linear oligopeptide can function as an epitope which can be recognized by anti-FLAG M2. When the LC is modified with 50 μM of FLAG and then exposed to an aqueous solution containing anti-FLAG, anti-FLAG binds to the immobilized FLAG epitope and triggers orientational transition of LC. Because of the optical birefringence of the LC, the orientational transition is accompanied by changes in the optical images of LC from dark to bright under crossed polarizers. The detection limit for the system is 27 ng/mL of anti-FLAG, and the response time is <1 h. The binding of anti-FLAG to its motif FLAG oligopeptide is also very specific. When a variant epitope CDAKDDDDK is used, no apparent optical response can be observed after the addition of anti-FLAG.

Magnetically complexed collagen nanocomposites

Rare-earth ions with unfilled 4f shells, Gd3+ (J = ) and Dy3+ (J = ) are bound to glutamic acid residues at the ends of long linear oligopeptides derived from those in naturally occurring collagen proteins. The peptide, which folds into a triple helix about 10 nm long, consists of a sequence 36 amino acids long. The rare-earth–collagen complex self-assembles into layers through a smectic A liquid crystalline phase. The smectic layered structure is retained on drying, and the acidic peptide end blocks localize the rare-earth ions in sheets approximately 1–2 nm thick separated by the collagen-like peptide of the complex. X-ray crystallographic, scanning electron microscopy and optical studies demonstrate the liquid crystallinity of the peptides and the incorporation of the rare-earth ions into sheets between the smectic layers. Magnetic susceptibility (2 K ≤ T ≤ 300 K) and low-temperature isothermal magnetization (0 T ≤ H ≤ 5 T) show the rare-earth–collagen complexes are paramagnetic in the rare-earth concentration range studied (not more than 0.3–0.4 Gd or Dy ion per molecule). This technique of bonding rare-earth ions to oligopeptides, and using the oligopeptide mesophase behaviour to organize attached ions, can be used to tether other rare-earth and/or transition-metal ions, creating layered magnetic structures. The interlayer spacing is dictated solely by the intervening oligopeptide length.

Does the Arg-Gly-Asp (RGD) adhesion sequence play a role in mediating sperm interaction with the human endosalpinx?

Sperm from several species, including the human, make direct contact with the endosalpinx. Although this is known to be beneficial to sperm function, the specific mechanisms mediating the adhesion are poorly understood. Short linear oligopeptides containing the amino acid sequence Arg-Gly-Asp (RGD) or a scrambled sequence (GRGES) were incorporated into an established sperm-endosalpingeal binding assay. In addition, the ability of fluorescent latex beads coated with an RGD oligopeptide to bind specifically to sperm and/or epithelium was also determined. Significantly fewer sperm associated per field of isthmic epithelium in the presence of 62.5 micro mol/l GRGDTP (1.18 +/- 0.41; mean +/- SEM, P < 0.05) and 250 micro mol/l RGDV (1.17 +/- 0.29; P < 0.01) compared with the control incubation (3.34 +/- 0.45). There was no difference in sperm binding to ampullary epithelium in the presence of any of the oligopeptides tested. Moreover, no beads were observed bound to sperm whereas significantly more RGD-coupled beads bound to isthmic epithelium compared with ampullary epithelium (1.47 +/- 0.26 versus 0.72 +/- 0.16 P < 0.01) and this increased in a dose-dependent manner. These findings indicate that the recognition between the RGD sequence and integrin receptors may contribute to the interaction between sperm and the human endosalpinx in the isthmic but not in the ampullary region of the uterine tube.

Novel cyclic and linear oligopeptides that bind to integrin β1 chain and either inhibit or costimulate T lymphocytes

There is a redundancy of cellular β1 integrin (very late antigen or VLA) receptors that mediate interactions between different extracellular matrix proteins (ECMP) and T lymphocytes. This suggests that antagonists targeted at individual VLA receptors may be of limited therapeutic efficacy in T cell-mediated diseases and that agents such as monoclonal antibody 4B4, which bind to the common integrin β1 chain and inhibit interactions between effector T cells and a range of ECMP, may be of greater therapeutic interest if toxicity can be avoided. We have therefore sought proof of principle as to whether small molecules that interact with the integrin β1 chain at or near the 4B4 binding site can modulate T cell costimulation and adhesion in the presence of type I collagen or fibronectin (FN). Two phage display libraries, each expressing more than 10 9 independent cyclic or linear 7-mer peptides, were used to identify molecules of interest by an enrichment process involving specific recovery of phage bound to a human T cell line by elution with a large excess of 4B4 antibody. Novel cyclic and linear peptides have thus been identified and found to inhibit interactions between T cells and both type I collagen and fibronectin. A separate cyclic peptide was found to costimulate T cells in a β1 integrin-dependent manner. These findings form a basis for the development of small molecules that interact in inhibitory or stimulatory capacities with the common integrin β1 chain, and may be of interest as therapeutic antagonists or immunologic adjuvants.

First Rigid Peptide Foldamers with an Alternating Cis−Trans Amide Sequence. An Oligomeric Building Block for the Construction of New Helices, Large-Ring Cyclic Correlates, and Nanotubes

As part of a program evaluating homochiral and heterochiral amino- and carboxylic acid-substituted γ-lactams as conformationally constrained dipeptide building blocks, we have synthesized by the solid-phase technique and assessed by X-ray diffraction the crystal-state structure of the terminally blocked homotrimer from (2S,4R)-4-amino-5-oxopyrrolidine-2-carboxylic acid, characterized by a unique, alternating cis−trans amide sequence. Using computer modeling, we also showed that the rigid conformation of the trimer can be exploited as a template to construct novel linear oligopeptide foldamers and large-ring cyclic correlates with self-recognizing properties.

Elucidation of Aluminum−Fulvic Acid Interactions by Gas-Phase Hydrogen/Deuterium (H/D) Exchange and Electrospray Fourier Transform Ion Cyclotron Resonance Mass Spectrometry (ESI FT-ICR)

A gas-phase hydrogen/deuterium (H/D) exchange reaction technique using electrospray ionization Fourier transform ion cyclotron resonance (ESI FT-ICR) mass spectrometry to study the interactions bet...

The effect of clay structure on peptide bond formation catalysis

The catalytic efficiency in peptide bond formation of various clays was tested by reactions of glycine (gly), diglycine (gly 2), glycine+alanine (ala), gly 2+ala. The main effects of clay structure and composition resulted as following: (1) Clay composition influences the activation of reactant molecules at clay particle edges. (2) Acidity (basicity) of the clay surface can change on the state of the reactant. (3) The clay structure is related to suspension stability and thus accessibility of clay catalytic sites. Mg-rich trioctahedral clays hectorite (smectite) and talc are the most efficient catalysts. Oligomerization of gly and gly 2 proceeds on all clays, whereas oligopeptides including ala units are formed with much lower yields and only on the most efficient catalysts. Besides dipeptides and other linear peptides, also cyclic anhydride (diketopiperazine) is formed with relatively high yields from diglycine. Cyclic anhydrides can directly act in the formation of the linear oligopeptides by ring opening molecular rearrangement and addition of another amino acid (oligopeptide).