Structural Reorganization Mechanism of the Aβ Fibril Mediated by -Substituted Oligopyrrolamide ADH-353.

The inhibition of amyloid-β (Aβ) fibrillation and clearance of Aβ aggregates have emerged as a potential pharmacological strategy to alleviate Aβ aggregate-induced neurotoxicity in Alzheimer's disease (AD). Maity et al. shortlisted ADH-353 from a small library of positively charged -substituted oligopyrrolamides for its notable ability to inhibit Aβ fibrillation, disintegrate intracellular cytotoxic Aβ oligomers, and alleviate Aβ-induced cytotoxicity in the SH-SY5Y and N2a cells.

Exploring the Impact of C-Terminal Based Pentapeptides on the Disassembly of Aβ Fibrils.

An effective therapeutic strategy to suppress Alzheimer's disease (AD) progression is to disrupt β-sheet rich neurotoxic soluble amyloid-β (Aβ) aggregates. Previously, we identified new pentapeptides (RVVPI and RIAPA) with notably enhanced ability to block Aβ aggregation as compared to Aβ C-terminal derived peptide RIIGL using integrated computational protocol. In this work, the potential of RIIGL, RVVPI, and RIAPA for the structural destabilization of Aβ protofibril was assessed by molecular dynamics (MD) simulations and in vitro studies.

Factor defining the effects of tetraalkylammonium chloride on stability, folding, and dynamics of horse cytochrome c.

This article describes the molecular mechanism by which tetraalkylammonium chloride ([RN]Cl: R- = methyl (Me), ethyl (Et), propyl (Pr),butyl (Bu)) modulates the stability, folding, and dynamics of cytochrome c (Cyt c). Analysis of [RN]Cl effects on thermal/chemical denaturations, millisecond refolding/unfolding kinetics, and slow CO-association kinetics of Cyt c without and with denaturant providing some significant results: (i) [RN]Cl decreasing the unfolding free energy estimated by thermodynamic and kinetic analysis of thermal/chemical denaturation curves and kinetic chevrons (Log k-[GdmCl]) of Cyt c, respectively (ii) hydrophobicity of R-group of [RN]Cl, preferential inclusion of [RN]Cl at the protein surface, and destabilizing enthalpic attractive interactions of [MeN]Cl and steric entropic interactions of [EtN]Cl,[PrN]Cl and [BuN]Cl with protein contribute to [RN]Cl-induced decrease thermodynamic stability of Cyt c (iii) [RN]Cl exhibits an additive effect with denaturant to decrease thermodynamic stability and refolding rates of Cyt c (iv) low concentrations of [RN]Cl (≤ 0.5 M) constrain the motional dynamics while the higher concentrations (>0.

Harnessing the Therapeutic Potential of Peptides for Synergistic Treatment of Alzheimer's Disease by Targeting Aβ Aggregation, Metal-Mediated Aβ Aggregation, Cholinesterase, Tau Degradation, and Oxidative Stress.

Alzheimer's disease (AD) is a progressive multifaceted neurodegenerative disease and remains a formidable global health challenge. The current medication for AD gives symptomatic relief and, thus, urges us to look for alternative disease-modifying therapies based on a multitarget directed approach. Looking at the remarkable progress made in peptide drug development in the last decade and the benefits associated with peptides, they offer valuable chemotypes [multitarget directed ligands (MTDLs)] as AD therapeutics.

Insights into the baicalein-induced destabilization of LS-shaped Aβ protofibrils using computer simulations.

Amyloid-β (Aβ) peptides aggregate spontaneously into various aggregating species comprising oligomers, protofibrils, and mature fibrils in Alzheimer's disease (AD). Disrupting β-sheet rich neurotoxic smaller soluble Aβ oligomers formed at early stages is considered a potent strategy to interfere with AD pathology. Previous experiments have demonstrated the inhibition of the early stages of Aβ aggregation by baicalein; however, the molecular mechanism behind inhibition remains largely unknown.

design and identification of new peptides for mitigating hIAPP aggregation in type 2 diabetes.

The aberrant misfolding and self-aggregation of human islet amyloid polypeptide (hIAPP or amylin) into cytotoxic aggregates are implicated in the pathogenesis of type 2 diabetes (T2D). Among various inhibitors, short peptides derived from the amyloidogenic regions of hIAPP have been employed as hIAPP aggregation inhibitors due to their low immunogenicity, biocompatibility, and high chemical diversity. Recently, hIAPP fragment HSSNN was identified as an amyloidogenic sequence and displayed higher antiproliferative activity to RIN-5F cells.

Multiepitope glycan based laser assisted fluorescent nanocomposite with dual functionality for sensing and ablation of .

() infection is becoming a severe health hazard and needs early diagnosis with high specificity. However, the non-specific binding of a biosensor is a challenge to the current bacterial detection system. For the first time, we chemically synthesized a galactose tripod (GT) as a -specific ligand.

Identification of new pentapeptides as potential inhibitors of amyloid-β aggregation using virtual screening and molecular dynamics simulations.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease mainly characterized by extracellular accumulation of amyloid-β (Aβ) peptide. Previous studies reported pentapeptide RIIGL as an effective inhibitor of Aβ aggregation and neurotoxicity induced by Aβ aggregates. In this work, a library of 912 pentapeptides based on RIIGL has been designed and assessed for their efficacy to inhibit Aβ aggregation using computational techniques.

Unveiling How Hydroxytyrosol Destabilizes α-Syn Oligomers Using Molecular Simulations.

The etiology of Parkinson's disease (PD) is mainly linked to the α-synuclein (α-Syn) fibrillogenesis. Hydroxytyrosol (HT), also known as 3,4-dihydroxyphenylethanol, is a naturally occurring polyphenol, found in extra virgin olive oil, and has been shown to have cardioprotective, anticancer, antiobesity, and antidiabetic properties. HT has neuroprotective benefits in neurodegenerative diseases and lessens the severity of PD by reducing the aggregation of α-Syn and destabilizing the preformed toxic α-Syn oligomers.

Salmonella typhimurium detection and ablation using OmpD specific aptamer with non-magnetic and magnetic graphene oxide.

Foodborne diseases have increased in the last few years due to the increased consumption of packaged and contaminated food. Major foodborne bacteria cause diseases such as diarrhea, vomiting, and sometimes death. So, there is a need for early detection of foodborne bacteria as pre-existing detection techniques are time-taking and tedious.

Triazole-Peptide Conjugate as a Modulator of Aβ-Aggregation, Metal-Mediated Aβ-Aggregation, and Cytotoxicity.

Amyloid-β (Aβ) aggregation plays a key role in the pathogenesis of Alzheimer's disease (AD). Along with this, the presence of redox-active metals like Cu further enhances Aβ aggregation, oxidative stress, and cellular toxicity. In this study, we have rationally designed, synthesized, and evaluated a series of triazole-peptide conjugates as potential promiscuous ligands capable of targeting different pathological factors of AD.

Structural and molecular insights into tacrine-benzofuran hybrid induced inhibition of amyloid-β peptide aggregation and BACE1 activity.

Amyloid-β (Aβ) aggregation and β-amyloid precursor protein cleaving enzyme 1 (BACE1) are the potential therapeutic drug targets for Alzheimer's disease (AD). A recent study highlighted that tacrine-benzofuran hybrid C1 displayed anti-aggregation activity against Aβ peptide and inhibit BACE1 activity. However, the inhibition mechanism of C1 against Aβ aggregation and BACE1 activity remains unclear.

Unravelling the destabilization potential of ellagic acid on α-synuclein fibrils using molecular dynamics simulations.

The aberrant deposition of α-synuclein (α-Syn) protein into the intracellular neuronal aggregates termed Lewy bodies and Lewy neurites characterizes the devastating neurodegenerative condition known as Parkinson's disease (PD). The disruption of pre-existing disease-relevant α-Syn fibrils is recognized as a viable therapeutic approach for PD. Ellagic acid (EA), a natural polyphenolic compound, is experimentally proven as a potential candidate that prevents or reverses the α-Syn fibrillization process.

Mechanistic insights into the mitigation of Aβ aggregation and protofibril destabilization by a D-enantiomeric decapeptide rk10.

According to clinical studies, the development of Alzheimer's disease (AD) is linked to the abnormal aggregation of amyloid-β (Aβ) peptides into toxic soluble oligomers, protofibrils as well as mature fibrils. The most acceptable therapeutic strategy for the treatment of AD is to block the Aβ aggregation. Sun and co-workers have reported a decapeptide, D-enantiomeric RTHLVFFARK-NH (rk10), which acts as a potent inhibitor of Aβ aggregation and efficiently disaggregates pre-assembled Aβ fibrils.

Near-Miss Incidents in Obstetric Patients Admitted to an Intensive Care Unit of a Tertiary Care Center in Eastern India: A Retrospective Cohort Study.

Aim: Obstetric patients presenting to the intensive care units (ICU) with or without underlying medical or surgical comorbidities can be a challenge to both the treating obstetrician and the intensivist. They occasionally present with near-miss events which if left untreated, can result in death.

Objectives: To study the prevalence, indications of ICU admissions, near-miss events, and their effect on mortality in obstetric and puerperal patients

Material & Methods: We conducted a retrospective analysis of the health records of all the obstetric and puerperal patients (pregnant and until 6 weeks postpartum) admitted to our tertiary care hospital from January 2019 to December 2020.

An α-helix mimetic oligopyridylamide, ADH-31, modulates Aβ monomer aggregation and destabilizes protofibril structures: insights from molecular dynamics simulations.

Alzheimer's disease (AD), an epidemic growing worldwide due to no effective medical aid available in the market, is a neurological disorder. AD is known to be directly associated with the toxicity of amyloid-β (Aβ) aggregates. In search of potent inhibitors of Aβ aggregation, Hamilton and co-workers reported an α-helix mimetic, ADH-31, which acts as a powerful antagonist of Aβ42 aggregation.

Effect of imidazolium based ionic liquids on CO-association dynamics and thermodynamic stability of Ferrocytochrome c.

Analysis of kinetic and thermodynamic parameters measured for CO-association reaction of Ferrocytochrome c (Ferrocyt c) under variable concentrations of 1-butyl-3-methylimidazolium with varying anion ([Bmim]X) (X = Cl, I, Br, HSO) at pH 7 revealed that the low concentration of [Bmim]X (≤0.5 M) constrains the CO-association dynamics of Ferrocyt c and typically follows the order: [Bmim]HSO > [Bmim]Cl > [Bmim]Br > [Bmim]I. At relatively higher concentrations (>0.

Targeting Human Islet Amyloid Polypeptide Aggregation and Toxicity in Type 2 Diabetes: An Overview of Peptide-Based Inhibitors.

Type 2 diabetes (T2D) is a chronic metabolic disease characterized by insulin resistance and a progressive loss of pancreatic islet β-cell mass, which leads to insufficient secretion of insulin and hyperglycemia. Emerging evidence suggests that toxic oligomers and fibrils of human islet amyloid polypeptide (hIAPP) contribute to the death of β-cells and lead to T2D pathogenesis. These observations have opened new avenues for the development of islet amyloid therapies for the treatment of T2D.

Impact of Mutations on the Conformational Transition from α-Helix to β-Sheet Structures in Arctic-Type Aβ: Insights from Molecular Dynamics Simulations.

The amyloid-β (Aβ) protein aggregation into toxic oligomers and fibrils has been recognized as a key player in the pathogenesis of Alzheimer's disease. Recent experiments reported that a double alanine mutation (L17A/F19A) in the central hydrophobic core (CHC) region of [G22]Aβ (familial Arctic mutation) diminished the self-assembly propensity of [G22]Aβ. However, the molecular mechanism behind the decreased aggregation tendency of [A17/A19/G22]Aβ is not well understood.

How Does the Mono-Triazole Derivative Modulate Aβ Aggregation and Disrupt a Protofibril Structure: Insights from Molecular Dynamics Simulations.

Clinical studies have identified that abnormal self-assembly of amyloid-β (Aβ) peptide into toxic fibrillar aggregates is associated with the pathology of Alzheimer's disease (AD). The most acceptable therapeutic approach to stop the progression of AD is to inhibit the formation of β-sheet-rich structures. Recently, we designed and evaluated a series of novel mono-triazole derivatives -, where compound was identified as the most potent inhibitor of Aβ aggregation and disaggregates preformed Aβ fibrils significantly.

Targeting the Dimerization of the Main Protease of Coronaviruses: A Potential Broad-Spectrum Therapeutic Strategy.

A new coronavirus (CoV) caused a pandemic named COVID-19, which has become a global health care emergency in the present time. The virus is referred to as SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) and has a genome similar (∼82%) to that of the previously known SARS-CoV (SARS coronavirus). An attractive therapeutic target for CoVs is the main protease (M) or 3-chymotrypsin-like cysteine protease (3CL), as this enzyme plays a key role in polyprotein processing and is active in a dimeric form.

Effect of Piedmont mutation (L34V) on the structure, dynamics, and aggregation of Alzheimer's Aβ peptide.

The amyloid-β (Aβ) aggregation in the brain has been associated with the development of Alzheimer's disease (AD). The previous studies have reported that Piedmont mutation (L34V) increases the rate of Aβ aggregation. However, the underlying molecular mechanism of the effect of L34V mutation on Aβ structure, dynamics, and aggregation remains largely unclear.

Interactions of a multifunctional di-triazole derivative with Alzheimer's Aβ monomer and Aβ protofibril: a systematic molecular dynamics study.

Amyloid aggregation modulators offer a promising treatment strategy for Alzheimer's disease (AD). We have recently reported a novel di-triazole based compound 6n as a multi-target-directed ligand (MTDL) against AD. 6n effectively inhibits Aβ42 aggregation, metal-induced Aβ42 aggregation, reactive oxygen species (ROS) generation, and rescues SH-SY5Y cells from Aβ42 induced neurotoxicity.

Molecular insights into the inhibitory mechanism of bi-functional bis-tryptoline triazole against β-secretase (BACE1) enzyme.

The β-site amyloid precursor protein-cleaving enzyme 1 (β-secretase, BACE1) is involved in the formation of amyloid-β (Aβ) peptide that aggregates into soluble oligomers, amyloid fibrils, and plaques responsible for the neurodegeneration in Alzheimer disease (AD). BACE1 is one of the prime therapeutic targets for the design of inhibitors against AD as BACE1 participate in the rate-limiting step in Aβ production. Jiaranaikulwanitch et al.

-guided identification of potential inhibitors against βm aggregation in dialysis-related amyloidosis.

In dialysis-related amyloidosis (DRA), misfolding of β-microglobulin (βm) leads to amyloid fibril deposition mainly in the skeletal joints seriously affecting their functionality. The identification and characterization of small-molecules that bind βm and possibly inhibit its aggregation remain unexplored. In the present study, a ligand-based virtual screening approach and molecular dynamics (MD) simulations were employed to explore potent small-molecule inhibitors against βm aggregation.