Structural Changes Of Peptides Research Articles

Effect of hydroxyethyl starch on drug stability and release of semaglutide in PLGA microspheres

The degradation of peptide drugs limits the application of peptide drug microspheres. Structural changes of peptides at the water–oil interface and the destruction of their spatial structure in the complex microenvironment during polymer degradation can affect drug release and in vivo biological activity. This study demonstrates that adding hydroxyethyl starch (HES) to the internal aqueous phase (W1) significantly enhances the stability of semaglutide and optimizes its release behavior in PLGA microspheres. The results showed that this improvement was due to a spontaneous exothermic reaction (ΔH = −132.20 kJ mol−1) facilitated by hydrogen bonds. Incorporating HES into the internal aqueous phase using the water-in-oil-in-water (W1/O/W2) emulsion method yielded PLGA microspheres with a high encapsulation rate of 94.38 %. Moreover, microspheres with HES demonstrated well-controlled drug release over 44 days, unlike the slower and incomplete release in microspheres without HES. The optimized h-MG2 formulation achieved a more complete drug release (83.23 %) and prevented 30.65 % of drug loss compared to the HES-free microspheres within the same period. Additionally, the optimized semaglutide microspheres provided nearly three weeks of glycemic control with adequate safety. In conclusion, adding HES to the internal aqueous phase improved the in-situ drug stability and release behavior of semaglutide-loaded PLGA microspheres, effectively increasing the peptide drug payload in PLGA microspheres.

Recent advances in self-assembled cyclic peptide-based smart nanostructures

Peptide chemistry has emerged as one of the growing fields of research. Peptide chemistry has positively impacted various areas, including biochemistry, medicine, hormonal therapy, drug delivery, food and the cosmetic industry, materials science, and nanotechnology, via the development of ways to change and imitate the shape and function of peptide structures. The structural changes of peptides and the employment of innovative synthetic techniques have left an indelible mark on a number of scientific disciplines. Numerous nanostructures based on simple and complicated peptides have been constructed so far; however, cyclic peptides have attracted a great deal of interest from the scientific community due to their wide range of applications and distinctive properties. These properties include self-assembly, morphogenesis, and charge distribution, among others. In addition, nanostructured cyclic peptides offer increased and effective performance due to their high stability, prolonged plasma half-life, membrane permeability, and efficient transport, among other attributes. Recent work indicates the manufacture of nanostructured cyclic peptides by chemical means. In this review, a brief investigation of the morphology of cyclic peptides was conducted. In addition, the therapeutic potential of these nanostructured cyclic peptides and the prognosis for a variety of potential applications are also discussed.

A Photoresponsive Artificial Viral Capsid Self-Assembled from an Azobenzene-Containing β-Annulus Peptide.

Photoinduced structural changes in peptides can dynamically control the formation and dissociation of supramolecular peptide materials. However, the existence of photoresponsive viral capsids in nature remains unknown. In this study, we constructed an artificial viral capsid possessing a photochromic azobenzene moiety on the peptide backbone. An azobenzene-containing β-annulus peptide derived from the tomato bushy stunt virus was prepared through solid-phase synthesis using Fmoc-3-[(3-aminomethyl)-phenylazo]phenylacetic acid. The azobenzene-containing β-annulus (β-Annulus-Azo) peptide showed a reversible trans/cis isomerization property. The β-annulus-azo peptide self-assembled at 25 μM into capsids with the diameters of 30–50 nm before UV irradiation (trans-form rich), whereas micrometer-sized aggregates were formed after UV irradiation (cis-form rich). The artificial viral capsid possessing azobenzene facilitated the encapsulation of fluorescent-labeled dextrans and their photoinduced release from the capsid.

Metal-Peptide Complexes as Promising Antibiotics to Fight Emerging Drug Resistance: New Perspectives in Tuberculosis.

In metal-peptide interactions, cations form stable complexes through bonds with coordinating groups as side chains of amino acids. These compounds, among other things, exert a wide variety of antimicrobial activities through structural changes of peptides upon metal binding and redox chemistry. They exhibit different mechanisms of action (MOA), including the modification of DNA/RNA, protein and cell wall synthesis, permeabilization and modulation of gradients of cellular membranes. Nowadays, the large increase in antibiotic resistance represents a crucial problem to limit progression at the pandemic level of the diseases that seemed nearly eradicated, such as tuberculosis (Tb). Mycobacterium tuberculosis (Mtb) is intrinsically resistant to many antibiotics due to chromosomal mutations which can lead to the onset of novel strains. Consequently, the maximum pharmaceutical effort should be focused on the development of new therapeutic agents and antimicrobial peptides can represent a valuable option as a copious source of potential bioactive compounds. The introduction of a metal center can improve chemical diversity and hence specificity and bioavailability while, in turn, the coordination to peptides of metal complexes can protect them and enhance their poor water solubility and air stability: the optimization of these parameters is strictly required for drug prioritization and to obtain potent inhibitors of Mtb infections with novel MOAs. Here, we present a panoramic review of the most recent findings in the field of metal complex-peptide conjugates and their delivery systems with the potential pharmaceutical application as novel antibiotics in Mtb infections.

Structural changes of a simple peptide—Trpzip-1—in aqueous solutions and the corresponding hydration phenomena under the influence of temperature

Trpzip-1, a simple β-hairpin, is a rare example of peptide with stable secondary structure and can be a convenient model to study temperature-related processes that potential prion or amyloid proteins undergo. Although its sequence is simple, the exact processes which the peptide undergoes in aqueous solutions are quite complex and not well understood. The selection of well-established experimental (DSC, FTIR) and theoretical methods allowed to describe, on the molecular level, the sequence of Trpzip-1 structural transitions. Our results we can indicate and explain peculiarities concerning initial oligomerization and two-step denaturation mechanism. The analysis of water structure surrounding the peptide at various temperatures reveals that the hydration sphere of its monomeric, oligomeric, and unfolded states is enhanced in comparison to the “bulk” water, but in each case, it exhibits different properties. Our observations may be of general nature in terms of structural changes of peptides and accompanying phenomena in solutions.

Temperature dependence of C-terminal carboxylic group IR absorptions in the amide I′ region

Studies of structural changes in peptides and proteins using IR spectroscopy often rely on subtle changes in the amide I′ band as a function of temperature. However, these changes can be obscured by the overlap with other absorptions, namely the side-chain and terminal carboxylic groups. The former were the subject of our previous report (Anderson et al., 2014). In this paper we investigate the IR spectra of the asymmetric stretch of α-carboxylic groups for amino acids representing all major types (Gly, Ala, Val, Leu, Ser, Thr, Asp, Glu, Lys, Asn, His, Trp, Pro) as well as the C-terminal groups of three dipeptides (Gly–Gly, Gly–Ala, Ala–Gly) in D2O at neutral pH. Experimental temperature dependent IR spectra were analyzed by fitting of both symmetric and asymmetric pseudo-Voigt functions. Qualitatively the spectra exhibit shifts to higher frequency, loss in intensity and narrowing with increased temperature, similar to that observed previously for the side-chain carboxylic groups of Asp. The observed dependence of the band parameters (frequency, intensity, width and shape) on temperature is in all cases linear: simple linear regression is therefore used to describe the spectral changes. The spectral parameters vary between individual amino acids and show systematic differences between the free amino acids and dipeptides, particularly in the absolute peak frequencies, but the temperature variations are comparable. The relative variations between the dipeptide spectral parameters are most sensitive to the C-terminal amino acid, and follow the trends observed in the free amino acid spectra. General rules for modeling the α-carboxylic IR absorption bands in peptides and proteins as the function of temperature are proposed.

Temperature dependence of amino acid side chain IR absorptions in the amide I' region

Amide I' IR spectra are widely used for studies of structural changes in peptides and proteins as a function of temperature. Temperature dependent absorptions of amino acid side-chains that overlap the amide I' may significantly complicate the structural analyses. While the side-chain IR spectra have been investigated previously, thus far their dependence on temperature has not been reported. Here we present the study of the changes in the IR spectra with temperature for side-chain groups of aspartate, glutamate, asparagine, glutamine, arginine, and tyrosine in the amide I' region (in D2O). Band fitting analysis was employed to extract the temperature dependence of the individual spectral parameters, such as peak frequency, integrated intensity, band width, and shape. As expected, the side-chain IR bands exhibit significant changes with temperature. The majority of the spectral parameters, particularly the frequency and intensity, show linear dependence on temperature, but the direction and magnitude vary depending on the particular side-chain group. The exception is arginine, which exhibits a distinctly nonlinear frequency shift with temperature for its asymmetric CN3H5(+) bending signal, although a linear fit can account for this change to within ~1/3 cm(-1). The applicability of the determined spectral parameters for estimations of temperature-dependent side-chain absorptions in peptides and proteins are discussed.

Structures of MART-1 26/27–35 Peptide/HLA-A2 Complexes Reveal a Remarkable Disconnect between Antigen Structural Homology and T Cell Recognition

Small structural changes in peptides presented by major histocompatibility complex (MHC) molecules often result in large changes in immunogenicity, supporting the notion that T cell receptors are exquisitely sensitive to antigen structure. Yet there are striking examples of TCR recognition of structurally dissimilar ligands. The resulting unpredictability of how T cells will respond to different or modified antigens impacts both our understanding of the physical bases for TCR specificity as well as efforts to engineer peptides for immunomodulation. In cancer immunotherapy, epitopes and variants derived from the MART-1/Melan-A protein are widely used as clinical vaccines. Two overlapping epitopes spanning amino acid residues 26 through 35 are of particular interest: numerous clinical studies have been performed using variants of the MART-1 26–35 decamer, although only the 27–35 nonamer has been found on the surface of targeted melanoma cells. Here, we show that the 26–35 and 27–35 peptides adopt strikingly different conformations when bound to HLA-A2. Nevertheless, clonally distinct MART-1 26/27–35-reactive T cells show broad cross-reactivity towards these ligands. Simultaneously, however, many of the cross-reactive T cells remain unable to recognize anchor-modified variants with very subtle structural differences. These dichotomous observations challenge our thinking about how structural information on unligated peptide/MHC complexes should be best used when addressing questions of TCR specificity. Our findings also indicate that caution is warranted in the design of immunotherapeutics based on the MART-1 26/27–35 epitopes, as neither cross-reactivity nor selectivity is predictable based on the analysis of the structures alone.

Solvation model induced structural changes in peptides. A quantum chemical study on Ramachandran surfaces and conformers of alanine diamide using the polarizable continuum model.

Potential energy surfaces of the model peptide HCO-L-Ala-NH2 were calculated using polarizable continuum model (PCM) for the description of aqueous solution at RHF/3-21G, RHF/6-31+G(d), and B3LYP/6-31+G(d) levels of theory. Energy minima were optimized at all three levels as well as at B3LYP/PCM/6-311++G(d,p) level of theory. Results were correlated to experimental data of protein structures retrieved from PDB SELECT. It is concluded that alanine residues of proteins are modeled better by PCM results than by gas-phase calculations on the alanine diamide model (frequently called alanine dipeptide model). The currently available version of the PCM model implemented in Gaussian 03 provides a reasonable alternative to anticipate solvation effects without the computational costs of introducing explicit solvent molecules into the model system. Frequencies calculated at RHF/PCM/6-31+G(d) and B3LYP/PCM/6-31+G(d) levels of theory show high correlation; thus, RHF results have their own merit.

Ultrafast Conformational Dynamics in Cyclic Azobenzene Peptides of Increased Flexibility

Structural changes of peptides containing the azobenzene dye 4-aminomethyl-phenylazobenzoic acid (AMPB) are studied with ultrafast spectroscopy. AMPB peptides are a new class of molecules where the photoisomerizable dye azobenzene is linked to the peptide moiety via a flexible methylene spacer. The ultrafast reactions in the femtosecond to nanosecond time domain are investigated for the optical switch AMPB, a linear and cyclic octapeptide, and a bicyclic octapeptide containing an additional disulfide bridge. These molecules with increasing conformational constraints are studied for the cis to trans and the trans to cis photoreactions. For the cis to trans reaction the isomerization of the chromophore occurs fast in the 1-ps range, whereas it is slower (10-ps range) in the trans to cis reaction. In all peptides the structural changes of the chromophore lead to modifications in the peptide structure in the 10-ps–1-ns time range. The results indicate that the chromophore AMPB acts simultaneously as a fast molecular switch and as a sensor for initial conformational dynamics in the peptide. Experiments in the mid-infrared range where the structural changes of the peptide backbone are directly observed demonstrate that the essential part of the structural dynamics in the bicyclic AMPB peptide occurs faster than 10 ns.

ChemInform Abstract: Photochemically Induced Electron Transfer (PET) Catalyzed Radical Cyclization: A Practical Method for Inducing Structural Changes in Peptides by Formation of Cyclic Amino Acid Derivatives.

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Structure of melittin bound to phospholipid micelles studied using hydrogen–deuterium exchange and electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry

The structure of melittin bound to dodecylphosphocholine (DPC) micelles was investigated using hydrogen–deuterium (H/D) exchange in conjunction with collision induced dissociation (CID) in an rf-only hexapole ion guide with electrospray ionization-Fourier transform ion cyclotron resonance mass spectrometry (ESI-FTICR MS). The deuterium incorporation into backbone amide hydrogens of melittin with or without DPC micelles was analyzed at different time points examining the mass of each fragment ion produced by hexapole CID. When melittin existed alone in aqueous solution, more than 80% of amide hydrogens was exchanged within 10 s, and the deuterium content in each fragment ion showed high values throughout the experiments. When melittin was bound to DPC micelles, the percentage of deuterium incorporation into the fragment decreased remarkably at any time point. It increased little by little as the exchange period prolonged, indicating that some stable structure was formed by the interaction with DPC. The results obtained here were consistent with the previous studies on the helical structure of melittin carried out by NMR and CD analyses. The strategy using H/D exchange and MS analysis might be useful for studying structural changes of peptides and proteins caused by phospholipid micelles. It could also be applied to membrane-bound proteins to characterize their structure.

Photochemically induced electron transfer (PET) catalyzed radical cyclization: a practical method for inducing structural changes in peptides by formation of cyclic amino acid derivatives.

A new radical cyclization reaction of unsaturated amino acid derivatives is presented. The reaction is induced by photoelectron transfer (PET) catalysis and proceeds, in comparison to commonly applied methods, under mild, nonoxidizing, and nontoxic conditions in neutral medium. This type of radical cyclization reaction can be used in peptide chemistry for inducing structural changes in peptides.