A critical review of the study on protein structure
Amyloid as a Depot for the Formulation of Long-Acting Drugs
Amyloids possess numerous properties that make their application relevant in nanotechnology. These properties include self- polymerization in a nucleation-dependent,they are stable in harsh physical,chemical and biochemical conditions amyloids as studied by(Fraga, Joo, H, & Tsai, 2016). Amyloid being protein aggregates are associated with neurodegenerative diseases, for instance, Alzheimer. Due to their stability and resistance to stimuli, Amyloid is suitable in the manufacture of long-acting drugs. An experiment conducted by (Jackson et al., 2012) to determine amyloidformulation by GnRH analogues through CR shows that upon prolonged incubation for about 30 days, some short-acting GnRH-analogs are cable of forming amyloids.
Conclusively, an amyloid-forming peptide drug has the capability to harbour drugs for a given period of time from which they are released in bits, thus forming the basis of a long-acting drug.
An Amino Acid Code for Beta Sheet Packing Structure
In a study conducted by (Mensink et al., 2017) to describe the beta-sheet packing,two types of four residual packaging cliques were investigated in a knob –socket analysis. The packaging cliques were depicted by contact between residues.Contact and side formed the basis of classification. Their analysis shows thatthe amino acid code for beta-sheet packing occurs between two adjacent hydrogen-bonded beta-sheets. To determine the complexity of beta-sheet packaging structure, the sequences specificity of beta-sheet packing can be revealed by the amino acid composition of the knob socket and pockets. As the XY: HG. XY: H+B side chain and main chain sockets that exhibits distinct amino acids form the composition for a tertiary packaging. The amino acid code is, therefore explained by the above relationships.
Beta Pleated Sheet Fibrils-A comparison of Native Amyloid with Synthetic Protein Fibrils
FTIR can be used to show the structural difference between beta-pleated sheet fibrils and native amyloid with synthetic protein fibril. A study conducted by (Moussa et al., 2016) to investigate whether or not there is a structural difference between these two, suggests that amyloids and beta-sheet differ in terms of molecular structure in the native protein. This is consistent with a further study conducted by (Prados-Rosales et al., 2019) also a structural difference between beta-pleated sheets fibrils and native amyloid with synthetic protein fibrils. Their findings indicate that these structures differ as illustrated by the amide I region of the infrared spectrum. Another study conducted by (Rocha, Flourier, Brezesinski, & do Carmo Pereira, 2012) indicates these two differs in terms of substantial structural reorganisation. An FTIR result from an analysis done by(Lomont et al., 2019) shows that the range of overlapping spectral regions for amyloid fibril starts from 1611cm-1 and ends at 1630cm-1 on the other hand, synthetic protein has an overlapping spectral region that ranges from 1630cm-1 to 1643cm-1. Beta pleated sheet and native amyloid differ in terms of the shape of the amide I band.The beta-sheet has a broader maximum in the amide band while native amyloid has narrow maxima.
Figure2: different in shape between native amyloid and beta-sheet in an amide I band(Lomont et al., 2019).
Determination of Beta-Sheet Crystallinity in Fibrous Proteins by Thermal Analysis and Infrared Spectroscopy
Beta sheet crystallinity in fibrous protein can be determined by thermal analysis and infrared spectroscopy through heating the films of the beta-pleated sheet above the glass transition temperature in the presence of methanol at a constant temperature. The findings of an experiment conducted by(Lomont et al., 2012) to determine beta-sheet crystallinity shows that as the crystalline beta-sheet forms there is a systematic in the heat capacity at the transitionalglass temperature. The finding further reveals that there is a linear correlation between beta-sheet content and heat capacity increment. To summarize, beta-sheet is determined systematically by exposing beta-pleated sheets to a constant temperature in the presence of methanol.
The Discovery of the alpha-helix and Beta Sheet
Alpha helix and beta-helix are protein blocked invented in the spring of 1951 two researcher Linus and Robert of California Institute of Technology. They were developed from crystal structures and chemical bonding that explored on planar peptide groups. Afurther study conducted by (Seuring et al., 2017)observed that helices made of planar amide groups with linear hydrogen bonds and measured bond dimensions could only give two outcomes which were the helix with 3.7 residues per turn and helix with 5.1 residues per turn later called alpha-helix and beta-helix respectively.
Exploration of the structure of Beta Sheet Structure and its Interactions with Chemical Model Systems
Beta sheets are networks of interconnected polypeptidestrands bound together by hydrogen bonds and form a greater percentage of protein composition. (Seuring et al., 2017)put an argument that the base pairing of biomolecular structures like DNA is as a result of hydrogen bonding that constitutes protein-protein aggregations. Afurther study reveals these beta-sheet interactions are fundamental for the studies of diseases such as cancer, AIDS and Alzheimer. (Seuring et al., 2017) suggests that chemical model systems can be used to investigate the behaviour of beta-sheets because they are less sophisticated compares to proteins.
Protein Drug Stability
Drug stability during long term storage and delivery are playing a significant role in the pharmaceutical industry in terms of their increased use of recombinant expressed therapeutic protein. A study conducted by (Taleb et al., 2017)shows that the adverse immunogenic side effects of drugs can be avoided by increasing drug stability and their efficiency during delivery systems. This is consistent with the study conducted by (Taleb et al., 2017)that the recent surge of interest in protein fibrillation can be used to minimize the aggregation and to misfolding ofproteins during storage. Theadverseimmunogenic side effects of drugs can also be achieved through control chemical modifications such as substitutions and acylation.
Stability and Analysis of Solid-State Forms in Pharmaceutical Powders
The quality of a pharmaceutical product is directly dependent on its solid-state form. A study conducted by (Taleb et al., 2017)reveals that the solid form can be affected during formulation and manufacturing. Thus there is a need to quantify and control the solid-state during process and storage. An experiment conducted by (Taleb et al., 2017) to analyze the solid-state of the pharmaceutical mixture using Raman spectroscopy showed that solid-state forms could easily be analyzed using the low frequency and time-gated Raman spectroscopy.
Structural Features of Amyloid Fibrils
Deposition of Amyloid fibrils formed from the various beta two tissues leads in the development of the dialysis-related amyloidosis due to its persistent with a highconcentration of myoglobin in the blood of patients with acute renal failure.(Taleb et al., 2017) found that the interactionbetween the dye with beta two fibrils decreases in the affinity and biochemistry of the interaction as a well as the shortening of the protein amino acid sequence as displayed by the fluorescence quantum yield and lifetime of the bound dye.
The Peptide hormone glucagon forms amyloid fibrils with two coexisting Beta strand conformation
Automatic resolution structure of fibrils is determined using NMR.an experiment conducted by (Lomont et al., 2017) reveals two sets of chemical shifts of coexistence of two strands of beta conformations. These two conformations differin terms of intermolecular contacts, and water accessibility brought about by alternating hydrogen bond in the fibril axis. In another conclusive research done by (Lomont et al., 2017)indicates that the two beta-sheets have a cross-section of an assembly of an asymmetric homodimer. The stability of this amyloid conformation is stable in an aromatic interaction environment. Further researchhighlights that inhibition of fibrillation due to mutagenesis stabilizes the drug.
Stability of Proteins in Aqueous Solution and Solid State
Stability of peptides and proteins in the different chemical and physical environment has been a challenge to formulation scientists; this is due to the various unique chemical,physical and biological behaviour exhibited by these portentous drugs. Aresearch conducted by (Lomont et al., 2017) suggests that glycerol enhances the stability of proteins in aqueoussolution. Their detailed analysis explains an electrostaticinteraction that orients glycerol particles at the protein and further dispersing glycerol. A study done by (Lomont et al., 2017) explain the drying mechanisms done to achieve stability in proteins in the solid-state, his findings show that various drying techniques such as freeze-drying or spray drying can be used to enhance the stability of the protein in solid-state for long term storage in pharmaceutical industries.
Protein Stability: Impact of Formulation excipients and manufacturing processes in protein-based pharmaceuticals
The free drying process has been adopted by most protein-based based pharmaceutical in order to increase the shelf life of protein-based drugs. Further studies reveal that mechanical agitation explores the packing and aggregation of proteins that are as a result of technological means that are important in the protein formulation. (Lomont et al., 2017) suggests that various technological process such as mixing dissolving produces strong stress on protein, thereby destabilizing them.
Immunogenicity of Therapeutic Protein Aggregates
Shipping,manufacturing and storage trigger proteins to have a propensity for aggregation.in an analysis on immunogenicity conducted by (Lomont et al., 2017)suggests that safety of patients is compromised by the presence of aggregates in drugs of protein in nature since they induce advance immune responses in patients.A further study carried out by,(Lomont et al., 2017)reveals that molecular properties of aggregates associated with immune activation are due to lack of understanding of the immunological responses as lack of standardized methods.
Improvement of Protein Analysis: Improve Techniques for protein analysis focusing on membrane proteins and hydrophobic peptides
Various techniques for protein analysis that focuses on membrane protein and hydrophobic peptides can be used to improve protein analysis.in an experiment conducted by(Lomont et al., 2017) to investigate techniques for protein analysis improvement showed that most of the cellular functions are triggered by membrane proteins. Their further analysis shows that membrane proteins are of two types, integral and peripheral membrane proteins. The peripheral protein-membrane improves protein analysis by signalling the cells while integral acts as receptors, channels and are used in cell adhesion and signalling.
Stable Liquid Glucagon Formulations for Rescue Treatment and Bi-Hormonal Closed-Loop Pancreas
Cases of hypoglycemia in persons with diabetes can be prevented by small doses of glycogen given subcutaneously in the research setting by an automated system. In a study by(Zhang, Zhang, & Yu, 2017), suggests that portable pumps cannot be used to store glucagon due to its instability, theirfurther findings showthat, at alkaline ph.,degrades drastically over time. This is consistent with the findings of(Zhang, Zhang, & Yu, 2017)that conversion of asparagine to aspartic acid resulting in delamination, which is a primary derivative pathway of glucagon.
Development of Stable Liquid Glucagon Formulations for Use in Artificial Pancreas
Maintenance of euglycemia by use of glucagon requires a fully automated artificialpancreas system in treating diabetes. An experiment done by (Zhang, Zhang, & Yu, 2017) to come up with a stable glucagon that is gel-free, free of fibrils and that has the requisite long term shelf life for storage show that, glucagon formed to have a long term stability of about two years at 5oc and a short term stability of 1 month at 37oc.
Specific Ion and Buffer Effects on Protein-Protein Interactions of a monoclonal antibody
Protein interactions require separating out contribution due to ionic screening, protein charge neutralization by ionic binding, and salt –in (out) behaviour since protein-protein interaction is affected by the better predictive ability of salt and buffer solution.(Zhang, Zhang, & Yu, 2017) found that, the specific ion and buffer effect on protein-protein interactions of a monoclonal antibody by measuring protein-protein interactions over an ionic strength range of 25 to 525Mm.there findings can be shown in the diagram below.
Figure 3: protein-protein interactions over a range of ionic strength (Zhang, Zhang, & Yu, 2017)
Consequences for the amyloid-beta structure
The amyloid-betastructure can be altered by the peptide surfactant interactions. The toxic aggregate formation depends on the conformation of the amyloid-betapeptide. Further studies reveal that beta-sheet formation is induced by uncharged micelles. Otherconsequences of peptide surfactant interaction include, at high concentration at higher surfaces peptides form beta-sheets.
Sulfates Dramatically Stabilize a Salt-Dependent Type of Glucagon Fibrils
Research work conducted by (Wilson, & Castle, 2018) suggests that ionic strength and environmental conditions are very sensitive in the structure of the resulting protein and the protein fibrillization.Further studies show thatfibrillization is less affected by cations, for instance, sulfates and anions at low ph.research results show that deviations in the concentration of anions adversely affects the stability of these fibrils.
Glucagon Fibril Polymorphism Reflects Differences Protofilamine Backbone Structure
Different morphologies are revealed when transmission electron microscopy is used to study amyloid fibrils formed by the 29– residue peptide glucagon at different concentrations.an experiment conducted to establish glucagon structure using ftir, and x-ray fibre diffraction shows a difference in terms in terms of Protofilaminebackboneregion, secondarystructures, chromophorealignment along the fibril axis
Protein secondary structures in water from second-derivative amide I infrared spectra
A study conducted in an aqueous solution at 20oc of 12 globular proteins reveals nine characteristic bands of vibration arising from amide groups of protein origin. The most important stretch observed of the nine vibrational bands in the amide I band originating from a C-O, this band has formed the basis for the study of the secondary structure of proteins in solution.
FTIR reveals structural differences between native beta-sheet proteins and amyloid fibrils
Results of a study conducted by (Wilson, & Castle, 2018) to establish the structural differencebetween native beta-sheet proteins and amyloid fibril using FTIR shows that amide I bands associated with native beta-sheet proteins are different from those resulting from amyloid fibrils. The difference comes about in terms of the thickness of the amide I bands revealed at different ranges in the absorption spectrum. The native beta-sheet has a broader amide band at 1630cm-1 while fibrils, on the contrary, has a narrower band at 1615cm-1
References
Fraga,., Joo, H., & Tsai, J. (2016). An amino acid code to define a protein’s tertiary packing surface. Proteins: Structure, Function, and Bioinformatics, 84(2), 201-216.
Gelernter, M. D., Smith, K. J., Liao, S. Y., Mandala, V. S., Dregni, A. J., Lamm, M. S., … & Su, Y. (2019). The peptide hormone glucagon forms amyloid fibrils with two coexisting β-strand conformations. Nature Structural & Molecular Biology, 26(7), 592-598.
Jackson, M. A., Caputo, N., Castle, J. R., David, L. L., Roberts, C. T., & Ward, W. K. (2012). Stable liquid glucagon formulations for rescue treatment and bi-hormonal closed-loop pancreas. Current diabetes reports, 12(6), 705-710.
Mensink, M. A., Frijlink, H. W., van der VoortMaarschalk, K., & Hinrichs, W. L. (2017). How sugars protect proteins in the solid-state and during drying (review): Mechanisms of stabilization in relation to stress conditions. European Journal of Pharmaceutics and Biopharmaceutics, 114, 288-295.
Moussa, E. M., Panchal, J. P., Moorthy, B. S., Blum, J. S., Joubert, M. K., Narhi, L. O., &Topp, E. M. (2016). Immunogenicity of therapeutic protein aggregates. Journal of pharmaceutical sciences, 105(2), 417-430.
Prados-Rosales, R. C., Aragoneses-Cazorla, G., Estevez, H., Garcia-Calvo, E., Machuca, A., &Luque-Garcia, J. L. (2019). Strategies for Membrane Protein Analysis by Mass Spectrometry. In Advancements of Mass Spectrometry in Biomedical Research (pp. 289-298). Springer, Cham.
Rocha, S., Loureiro, J. A., Brezesinski, G., & do Carmo Pereira, M. (2012). Peptide–surfactant interactions: Consequences for the amyloid-beta structure. Biochemical and biophysical research communications, 420(1), 136-140.
Lomont, J. P., Ostrander, J. S., Ho, J. J., Petti, M. K., &Zanni, M. T. (2017). Not all β-sheets are the same: Amyloid infrared spectra, transition dipole strengths, and couplings investigated by 2D IR spectroscopy. The Journal of Physical Chemistry B, 121(38), 8935-8945.
Securing, C., Verasdonck, J., Ringler, P., Cadalbert, R., Stahlberg, H., Böckmann, A., … &Riek, R. (2017). Amyloid fibril polymorphism: almost identical on the atomic level, mesoscopically very different. The Journal of Physical Chemistry B, 121(8), 1783-1792.
Taleb, N., Coriati, A., Khazzaka, C., Bayonne, J., Messier, V., &Rabasa-Lhoret, R. (2017). Stability of commercially available glucagon formulation for dual-hormone artificial pancreas clinical use. Diabetes technology & therapeutics, 19(10), 589-594.
Wilson, L. M., & Castle, J. R. (2018). Stable liquid glucagon: beyond emergency hypoglycemia rescue. Journal of diabetes science and technology, 12(4), 847-853.
Zhang, J., Zhang, X., Zhang, F., & Yu, S. (2017). Solid-film sampling method for the determination of protein secondary structure by Fourier transforms infrared spectroscopy. Analytical and bioanalytical chemistry, 409(18), 4459-4465.
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