Stabilizing proteins to prevent conformational changes required for amyloid fibril formation

Abstract

Amyloid fibrillation is associated with several human maladies, such as Alzheimer’s, Parkinson’s, Huntington’s diseases, prions, amyotrophic lateral sclerosis, and type 2 diabetes diseases. Gaining insights into the mechanism of amyloid fibril formation and exploring novel approaches to fibrillation inhibition are crucial for preventing amyloid diseases. Here, we hypothesized that ligands capable of stabilizing the native state of query proteins might prevent protein unfolding, which, in turn, may reduce the propensity of proteins to form amyloid fibrils. We demonstrated the efficient inhibition of amyloid formation of the human serum albumin (HSA) (up to 85%) and human insulin (up to 80%) by a nonsteroidal anti‐inflammatory drug, ibuprofen (IBFN). IBFN significantly increases the conformational stability of both HSA and insulin, as confirmed by differential scanning calorimetry (DSC). Moreover, increasing concentration of IBFN boosts its amyloid inhibitory propensity in a linear fashion by influencing the nucleation phase as assayed by thioflavin T fluorescence, transmission electron microscopy, and dynamic light scattering. Furthermore, circular dichroism analysis supported the DSC results, showing that IBFN binds to the native state of proteins and almost completely prevents their tendency to lose secondary and tertiary structures. Cell toxicity assay confirms that species formed in the presence of IBFN are less toxic to neuronal cells (SH‐SY5Y). These results demonstrate the feasibility of using a small molecule to stabilize the native state of proteins, thereby preventing the amyloidogenic conformational changes, which appear to be the common link in several human amyloid diseases.

DARK Classics in Chemical Neuroscience: Opium, a Friend or Foe

“…Previously, our group has reported the effect of small molecules in preventing amyloid formation in proteins and their ability to protect neuronal cells against amyloid induced cytotoxicity. − In this Review, we discuss some basic information regarding opium, opium content and mechanism of action, pharmacology of opium derivatives, the role of opium in prevention of neurodegeneration, and adverse effects of opium derivatives on the neuronal health, and we attempt to widely disperse data into one easily accessible format for the “Classics in Chemical Neuroscience” series.…”

Spectroscopic and computational exploration of hypoxanthine riboside interacting with plasma albumin

“…It can be seen that the α‐helix content decreased from 59.6% to 57.2%, while β ‐strand content increased from 5.9% to 6.9% when the HXR concentration was 100 times as high as that of HSA, suggesting the effect of HXR on β ‐strands was more obvious than on α‐helices. This difference could be explained because, as mentioned in molecular modeling section, HXR was located in the cavity formed by the first six helixes in domain I, and this positioning meant that folding was maintained as it did not impinge into the inner part of the helix . Changes became smaller when β‐ CD was added together with HXR, this difference implied that some HXR molecules would have been trapped by β‐ CD and only the remainder could directly participate in the equilibrium between HXR and HSA.…”

Hypomyelinating Leukodystrophy 8 (HLD8)-Associated Mutation of POLR3B Leads to Defective Oligodendroglial Morphological Differentiation Whose Effect Is Reversed by Ibuprofen

“…Whether direct or indirect, many ibuprofen target molecules and pathways with protective effects have been described besides cyclooxygenases, such as Cox1/2 [ 25 ], which show antipyretic effects ( Table 2 ). Among them, one target is amyloid precursor protein (APP) or amyloid oligomers such as an APP pathological product peptide or other protein oligomers [ 35 , 36 , 37 , 38 ]. Ibuprofen inhibits APP secretion and binds pathological amyloid to decrease its toxicity.…”