Abstract
Looking through a historical lens, attention to the stabilization of pharmaceutical proteins/peptides has been dramatically increased. Human insulin is the most challenging and the most widely used pharmaceutical protein in the world. In this study, the protein and coumarin as a plant-derived phenolic compound and two coumarin analogs with different moieties were investigated to evaluate the protein fibrillation and cytotoxicity. The obtained data showed that with a change in environmental pH, the behavior of the compounds on the process of insulin fibrillation will be changed completely. Coumarin (C1) and its hydrophobic analog, 7-methyl coumarin (C2), in an acidic environment, inhibit insulin fibrillation, change the oligomerization state of insulin and produce fibrils with notable lateral interactions with low cytotoxicity. However, negatively-charged 3-trifluoromethyl coumarin (C3) without significant changes in insulin structure and by altering the oligomerization state of the protein, slightly accelerates hormone fibrillation. Also, the compounds showed a disulfide protecting role during protein aggregation. Regarding the toxicity of the fibrils, it was observed that in addition to the secondary structures of proteinous fibrils, the ability to destroy the cell membrane is also related to the length of the fibrils and their degree of lateral interactions. By and large, this work can be useful in finding a better formulation for bio-pharmaceutical macro-molecules.
Highlights
Some proteins/peptides aggregate/ brillate in the presence of environmental stresses.[1]
Bis-1-anilino-8-naphthalene sulfonate, Thio avin T (ThT), recombinant human insulin (UniProt ID P01308), 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), 1,4-dithiothreitol (DTT) and other chemicals were purchased from Sigma (Aldrich, Using a BioTek (USA))
The stabilities of the compounds were studied by recording obtained maximum emission wavelength during 20 h intervals by a Cary Eclipse uorescence spectrophotometer (Varian Cary Eclipse, USA) which armed with a Peltier unit to control the temperature
Summary
Some proteins/peptides aggregate/ brillate in the presence of environmental stresses.[1] There are several proteinopathies such as Parkinson's and Alzheimer's diseases that have been known to have a close relationship with the aggregation of functional or structural proteins.[2,3] protein misfolding, amorphous and morphous aggregations of these molecules are known as a big challenge in the industrial production of therapeutic proteins and peptides.[1,4] the stabilization of these biopharmaceutical products in different ways is an important eld in the world of biotechnology. Several studies have been carried out to increase the stability of therapeutic proteins. Some of the researchers used nano-mediated systems,[5,6,7] others tried to use proteinous chaperons to inhibit
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