Inhibition of primary and secondary nucleation alongwith disruption of amyloid fibrils and alleviation of associated cytotoxicity: A biophysical insight of a novel property of Chlorpropamide (an anti-diabetic drug).

Aggregation of physiologically synthesized soluble proteins to insoluble, cytotoxic fibrils is a pre-requisite for pathogenesis of amyloid associated disorders including Alzheimer's disease, non-systemic amyloidosis, Parkinson's disease, etc. Considerable advancement has been made to understand the mechanism behind aggregation process but till date we have no efficient cure and preventive therapy for associated diseases. Strategies to prevent protein aggregation are nevertheless many which have been proved promisingly successful in vitro.

Biophysical insight into the anti-fibrillation potential of Glyburide for its possible implication in therapeutic intervention of amyloid associated diseases.

Protein aggregation is an underlying cause of many neurodegenerative diseases. Also, the overlapping pathological disturbances between neurodegenerative diseases and type-2 diabetes mellitus have urged the scientific community to explore potential of already available anti-diabetic medications in impeding amyloid formation too. Recent study brief out promising potential of an anti-diabetic drug Glyburide(GLY) as an inhibitor of amyloid fibrillation utilizing several biophysical techniques, computational methods and imaging tools.

Chickpea Peptide: A Nutraceutical Molecule Corroborating Neurodegenerative and ACE-I Inhibition.

Chickpea seeds are the source of proteins in human nutrition and attribute some nutraceutical properties. Herein, we report the effects of chickpea seed bioactive peptide on albumin, insulin, lactoglobulin and lysozyme amyloid fibril formation. Employing thioflavin T (ThT) assays and circular dichroism (CD), amyloid structural binding transition was experimented to analyze the inhibition of amyloid fibril formation.

Populations of Tau Conformers Drive Prion-like Strain Effects in Alzheimer's Disease and Related Dementias.

Recent findings of diverse populations of prion-like conformers of misfolded tau protein expand the prion concept to Alzheimer's disease (AD) and monogenic frontotemporal lobar degeneration (FTLD)-MAPT P301L, and suggest that distinct strains of misfolded proteins drive the phenotypes and progression rates in many neurodegenerative diseases. Notable progress in the previous decades has generated many lines of proof arguing that yeast, fungal, and mammalian prions determine heritable as well as infectious traits. The extraordinary phenotypic diversity of human prion diseases arises from structurally distinct prion strains that target, at different progression speeds, variable brain structures and cells.

Cholic acid inhibits amyloid fibrillation: Interplay of protonation and deprotonation.

Amyloidopathies are the consequence of misfolding with subsequent aggregation affecting people worldwide. Irrespective of speedy advancement in the field of therapeutics no agent for treating amyloidopathies has been discovered and thus targeting amyloid fibrillation process via repositioning of small molecules can be fruitful. According to previous reports potential amyloid inhibitors possess unique features like, hydrophobicity, aromaticity, charge etc.

Mechanistic insight into inhibition of amyloid fibrillation of human serum albumin by Vildagliptin.

Protein aggregation leads to several human pathologies such as Alzheimer's disease (AD), type 2 diabetes (T2D), Parkinson's disease (PD), etc. Due to the overlap in the mechanisms of type 2 diabetes and brain disorders, common effective pharmacological interventions to treat both T2D and AD is under extensive research. Therefore, major aim of research is to repurpose already established treatment of diabetes to cure AD as well.

Structurally distinct external solvent-exposed domains drive replication of major human prions.

There is a limited understanding of structural attributes that encode the iatrogenic transmissibility and various phenotypes of prions causing the most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD). Here we report the detailed structural differences between major sCJD MM1, MM2, and VV2 prions determined with two complementary synchrotron hydroxyl radical footprinting techniques-mass spectrometry (MS) and conformation dependent immunoassay (CDI) with a panel of Europium-labeled antibodies. Both approaches clearly demonstrate that the phenotypically distant prions differ in a major way with regard to their structural organization, and synchrotron-generated hydroxyl radicals progressively inhibit their seeding potency in a strain and structure-specific manner.

On the binding reaction of loratadine with human serum acute phase protein alpha 1-acid glycoprotein.

Loratadine is an important anti-allergic drug. It is a second generation antihistamine drug used to treat allergic rhinitis, hay fever and urticaria. Human serum alpha 1-acid glycoprotein (AG) is an important acute phase protein and its serum concentration is found to increase in inflammation and acute response.

Biophysical insight into the interaction of levocabastine with human serum albumin: spectroscopy and molecular docking approach.

Interaction of levocabastine with human serum albumin (HSA) is investigated by applying fluorescence spectroscopy, circular dichroism spectroscopy and molecular docking methods. Levocabastine is an important drug in treatment of allergy and currently a target drug for drug repurposing to treat other diseases like vernal keratoconjuctivitis. Fluorescence quenching data revealed that levocabastine bind weakly to protein with binding constant in the order of 10 M.

Amyloid Oligomers, Protofibrils and Fibrils.

Amyloid diseases are of major concern all over the world due to a number of factors including: (i) aging population, (ii) increasing life span and (iii) lack of effective pharmacotherapy options. The past decade has seen intense research in discovering disease-modifying multi-targeting small molecules as therapeutic options. In recent years, targeting the amyloid cascade has emerged as an attractive strategy to discover novel neurotherapeutics.

Cytotoxic species in amyloid-associated diseases: Oligomers or mature fibrils.

Amyloid diseases especially, Alzheimer's disease (AD), is characterized by an imbalance between the production and clearance of amyloid-β (Aβ) species. Amyloidogenic proteins or peptides can transform structurally from monomers into β-stranded fibrils via multiple oligomeric states. Among various amyloid species, structured oligomers are proposed to be more toxic than fibrils; however, the identification of amyloid oligomers has been challenging due to their heterogeneous and metastable nature.

Both beta sheet breaker and alpha helix forming pentapeptide inhibits protein fibrillation: Implication for the treatment of amyloid disorders.

For the first time, the effect of two novel designed pentapeptides on amyloid growth of human insulin using combined biophysical, microscopic, cell viability and computational approaches. Collective experimental data from ThT, ANS, and TEM demonstrate that in spite of having contrasting features, both peptides can effectively inhibit amyloid formation by prolonging lag phase, slowing down aggregation rate, and reducing final fibril formation (up to 84.26% and 85.

Unravelling the inhibitory and cytoprotective potential of diuretics towards amyloid fibrillation.

Protein misfolding and deposition of aggregated proteins inside as well as outside of the cells have been associated with several neurotoxic and neurodegenerative disorders like Alzheimer's, Parkinson's and familial amyloid polyneuropathy etc. that could be controlled by anti-aggregation methodologies employing either inhibition or disaggregation of toxic aggregates. Also, the Alzheimer's disease develops in later life is somehow related to the high mid-life blood pressure.

Biophysical Elucidation of Amyloid Fibrillation Inhibition and Prevention of Secondary Nucleation by Cholic Acid: An Unexplored Function of Cholic Acid.

Protein misfolding and its deviant self-assembly to converge into amyloid fibrils is associated with the perturbation of cellular functions and thus with debilitating neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, etc. A great deal of research has already been carried out to discover a potential amyloid inhibitor that can slow down, prevent, or remodel toxic amyloids. In the present study with the help of a combination of biophysical, imaging, and computational techniques, we investigated the mechanism of interaction of cholic acid (CA), a primary bile acid, with human insulin and Aβ-42 and found CA to be effective in inhibiting amyloid formation.

Explication of bovine serum albumin binding with naphthyl hydroxamic acids using a multispectroscopic and molecular docking approach along with its antioxidant activity.

In the present investigation, the protein-binding properties of naphthyl-based hydroxamic acids (HAs), N-1-naphthyllaurohydroxamic acid (1) and N-1-naphthyl-p-methylbenzohydroxamic acid (2) were studied using bovine serum albumin (BSA) and UV-visible spectroscopy, fluorescence spectroscopy, diffuse reflectance spectroscopy-Fourier transform infrared (DRS-FTIR), circular dichroism (CD), and cyclic voltammetry along with computational approaches, i.e. molecular docking.

An In Vitro elucidation of the antiaggregatory potential of Diosminover thermally induced unfolding of hen egg white lysozyme; A preventive quest for lysozyme amyloidosis.

Protein misfolding diseases are associated with human pathologies. These neurodegenerative diseases remain challenging task for researchers because of their adverse effect on vital organs system. Lysozyme amyloidosis is also associated with multi-organ dysfunction.

Elucidating the inhibitory potential of Vitamin A against fibrillation and amyloid associated cytotoxicity.

Protein aggregation and amyloid fibrillation are associated with many serious human pathophysiologies like Alzheimer's, Parkinson's diseases, type II diabetes etc. A powerful strategy for controlling and understanding amyloid protein aggregation is the modulation of protein self-assembly. In this study, anti-fibrillation activity of vitamin A (VA) and its effect on the kinetics of amyloid formation of Aβ-42 peptide was investigated by employing various spectroscopic, imaging and computational approaches.

Molecular docking of Aβ peptide and its Iowa DN mutant using small molecule inhibitors: Possible mechanisms of Aβ-peptide inhibition.

Alzheimer's disease (AD) is the most common form of neurodegenerative diseases, characterized by the deposition of Aβ (amyloid beta) peptide. In this study, we have unravelled the interactions as well as anti amyloidogenic behaviour of 40 small molecule inhibitors with Aβ peptide and Iowa mutant DN-Aβ1 peptide at atomic level and their modes of binding by docking approaches. The binding mode between wild type peptide and drug is distinctly different from the Iowa-mutant-peptide and drug.

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

Opium has found great use medicinally for its analgesic properties and has been witnessed as one of the most popular medications used in psychiatry. Opium derivatives have been shown as efficacious for relieving pain and the treatment of epileptic seizures, but progressive research toward their use in the treatment of neurodegenerative diseases remain elusive. To gain more insight into the other properties of opium such as anti-inflammatory properties, herein we discuss basic information regarding opium, opium content and mechanism of action, pharmacology of opium derivatives, the role of opium in the prevention of neurodegeneration, and adverse effects of opium derivatives on neuronal health.

Stabilizing proteins to prevent conformational changes required for amyloid fibril formation.

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.

Elucidating the Inhibitory Potential of Designed Peptides Against Amyloid Fibrillation and Amyloid Associated Cytotoxicity.

Inhibition of fibrillation process and disaggregation of mature fibrils using small peptide are the promising remedial strategies to combat neurodegenerative diseases. However, designing peptide-based drugs to target β-sheet-rich amyloid has been a major challenge. The current work describes, for the first time, the amyloid inhibitory potential of the two short peptides (selected on the basis of predisposition of their amino acid residues toward β-sheet formation) using combination of biophysical, imaging methods, and docking approaches.

Probing the binding of phenolic aldehyde vanillin with bovine serum albumin: Evidence from spectroscopic and docking approach.

The interactions of bovine serum albumin (BSA) with vanillin (VAN) were studied using UV-vis absorption, fluorescence, synchronous fluorescence, three dimensional fluorescence spectroscopy (3D), Fourier transform infrared spectroscopy (FTIR), circular dichroism (CD), and molecular docking techniques. The results revealed that VAN causes the static quenching of BSA by forming BSA-VAN complex. The thermodynamic parameters obtained using isothermal titration calorimetry (ITC) showed that the interaction between BSA and VAN is spontaneous and hydrogen bonding, van der Waals forces are mainly involved in stabilizing the complex.

Exploring the intermolecular interactions and contrasting binding of flufenamic acid with hemoglobin and lysozyme: A biophysical and docking insight.

The intermolecular interaction of flufenamic acid (Hfluf) with two model proteins i.e., hemoglobin and lysozyme was explored using fluorescence, UV-vis, circular dichroism, DLS, and molecular docking techniques.

Biophysical insights into the interaction of clofazimine with human alpha 1-acid glycoprotein: a multitechnique approach.

Alpha1-acid glycoprotein (AAG) is a major acute phase protein of human plasma. Binding of clofazimine to AAG is investigated using optical spectroscopy and molecular docking tools. We found significant quenching of intrinsic fluorescence of AAG upon the binding of clofazimine, binding mode is static with binding constant of 3.