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1.
Dalton Trans ; 53(28): 11914-11927, 2024 Jul 16.
Article in English | MEDLINE | ID: mdl-38958025

ABSTRACT

Currently, there are many uses of metal complexes, especially in the fields of medicinal chemistry and catalysis. Thus, fabrication of new complexes which perform as a catalyst and chemotherapeutic drug is always a beneficial addition to the literature. Herein, we report three heterocyclic thiosemicarbazone-based Pd(II) complexes [Pd(HL1)Cl] (C1), [Pd(L2)(PPh3)] (C2) and [Pd(L3)(PPh3)]Cl (C3) having coligands Cl and PPh3. Thiosemicarbazone ligands (H2L1, H2L2 and HL3) and the complexes (C1-C3) were characterized methodically using several spectroscopic techniques. Single-crystal X-ray diffraction methods reveal that the structural environment around the metal center of C2 is square planar, while for C1 and C3 it is a slighty distorted square plane. The supramolecular network of compounds was built via hydrogen bonds, C-H⋯π and π⋯π interactions. Density functional theory (DFT) study of the structure of the complexes supports experimental findings. The application of these complexes as catalysts toward Suzuki-Miyaura coupling reactions has been examined with various aryl halides and phenyl boronic acid in PEG 400 solvent. The complexes displayed good biomolecular interactions with DNA/protein, with a binding constant value of the order of 105 M-1. C3 showed greater binding efficacy toward these biomolecules than the other complexes, which might be due to the cationic nature of C3. Furthermore, antitumor activity of the complexes was studied against the human triple-negative breast cancer (TNBC) cell line MDA-MB-231. It was found that C3 was more toxic (IC50 = 10 ± 2.90 µM) toward MDA-MB-231 cells than the other complexes. A known chemotherapeutic drug, 5-fluorouracil, was included as positive control. The programmed cell death mechanism of C3 was confirmed. Additionally, complex-induced apoptosis was confirmed and occurred via a mitochondria-dependent (intrinsic) pathway.


Subject(s)
Antineoplastic Agents , Coordination Complexes , Palladium , Thiosemicarbazones , Palladium/chemistry , Palladium/pharmacology , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Thiosemicarbazones/chemistry , Thiosemicarbazones/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Coordination Complexes/chemical synthesis , Catalysis , Cell Line, Tumor , Drug Screening Assays, Antitumor , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Molecular Structure , Cell Proliferation/drug effects , Density Functional Theory , Models, Molecular , Apoptosis/drug effects
2.
Small ; : e2402953, 2024 Jun 24.
Article in English | MEDLINE | ID: mdl-38923392

ABSTRACT

While peptide-based drug development is extensively explored, this strategy has limitations due to rapid excretion from the body (or shorter half-life in the body) and vulnerability to protease-mediated degradation. To overcome these limitations, a novel strategy for the development of a peptide-based anticancer agent is introduced, utilizing the conformation switch property of a chameleon sequence stretch (PEP1) derived from a mycobacterium secretory protein, MPT63. The selected peptide is then loaded into a new porous organic polymer (PG-DFC-POP) synthesized using phloroglucinol and a cresol derivative via a condensation reaction to deliver the peptide selectively to cancer cells. Utilizing ensemble and single-molecule approaches, this peptide undergoes a transition from a disordered to an alpha-helical conformation, triggered by the acidic environment within cancer cells that is demonstrated. This adopted alpha-helical conformation resulted in the formation of proteolysis-resistant oligomers, which showed efficient membrane pore-forming activity selectively for negatively charged phospholipids accumulated in cancer cell membranes. The experimental results demonstrated that the peptide-loaded PG-DFC-POP-PEP1 exhibited significant cytotoxicity in cancer cells, leading to cell death through the Pyroptosis pathway, which is established by monitoring numerous associated events starting from lysosome membrane damage to GSDMD-induced cell membrane demolition. This novel conformational switch-based drug design strategy is believed to have great potential in endogenous environment-responsive cancer therapy and the development of future drug candidates to mitigate cancers.

3.
J Mater Chem B ; 11(28): 6646-6663, 2023 07 19.
Article in English | MEDLINE | ID: mdl-37366114

ABSTRACT

Quercetin (Qu), a potential bioflavonoid has gained considerable interest as a promising chemotherapeutic drug which can inhibit the proliferation of triple-negative breast cancer (TNBC) cells due to its regulation of the expression of tumor-suppressor gene metastasis and antioxidant property. Notably, Qu exhibits a very negligible cytotoxic effect on normal cells, even with high-dose treatment, while it is shows high affinity to TNBC. However, the efficiency of Qu is limited clinically due to its poor bioavailability, caused by its low aqueous solubility (2.15 µg mL-1 at 25 °C), rapid gastrointestinal digestion and chemical instability in alkaline and neutral media. Herein, polydopamine (PDA)-coated, NH2-PEG-NH2 and hyaluronic acid (HA)-functionalized Gd3+-doped Prussian blue nanocubes (GPBNC) are reported as a multifunctional platform for the codelivery of Qu as a chemotherapeutic agent and GPBNC as a photodynamic (PDT) and photothermal (PTT) agent with improved therapeutic efficiency to overcome theses barriers. PDA, NH2-PEG-NH2 and HA stabilize GPBNC@Qu and facilitate bioavailability and active-targeting, while absorption of near infrared (NIR) (808 nm; 1 W cm-2) induces PDT and PTT activities and dual T1-T2-weighted magnetic resonance imaging (MRI) with high relaxometric parameters (r1 10.06 mM-1 s-1 and r2 24.96 mM-1 s-1 at a magnetic field of 3 T). The designed platform shows a pH-responsive Qu release profile and NIR-induced therapeutic efficiency of ∼79% in 20 minutes of irradiation, wherein N-terminal gardermin D (N-GSDMD) and a P2X7-receptor-mediated pyroptosis pathway induces cell death, corroborating the up-regulation of NLRP3, caspase-1, caspase-5, N-GSDMD, IL-1ß, cleaved Pannexin-1 and P2X7 proteins. More interestingly, the increasing relaxivity values of Prussian blue nanocubes with Gd3+ doping have been explained on the basis of Solomon-Bloembergen-Morgan theory, considering inner- and outer-sphere relaxivity, wherein crystal defects, coordinated water molecules, tumbling rate, metal to water proton distance, correlation time, magnetisation value etc. play a significant role. In summary, our study suggests that GPBNC could be a beneficial nanocarrier for theranostic purposes against TNBC, while our conceptual study clearly demonstrates the role of various factors in increasing relaxometric parameters.


Subject(s)
Quercetin , Triple Negative Breast Neoplasms , Humans , Quercetin/pharmacology , MDA-MB-231 Cells , Triple Negative Breast Neoplasms/pathology , Magnetic Resonance Imaging/methods , Water , Caspases
4.
Commun Biol ; 6(1): 411, 2023 04 14.
Article in English | MEDLINE | ID: mdl-37059826
5.
J Biol Chem ; 299(5): 104653, 2023 05.
Article in English | MEDLINE | ID: mdl-36990217

ABSTRACT

Accumulating evidence suggests that amyloid plaque-associated myelin lipid loss as a result of elevated amyloid burden might also contribute to Alzheimer's disease. The amyloid fibrils are closely associated with lipids under physiological conditions; however, the progression of membrane remodeling events leading to lipid-fibril assembly remains unknown. Here we first reconstitute the interaction of amyloid Beta 40 (Aß-40) with myelin-like model membrane and show that the binding of Aß-40 induces extensive tubulation. To look into the mechanism of membrane tubulation, we chose a set of membrane conditions varying in lipid packing density and net charge that allows us to dissect the contribution of lipid specificity of Aß-40 binding, aggregation kinetics, and subsequent changes in membrane parameters such as fluidity, diffusion, and compressibility modulus. We show that the binding of Aß-40 depends predominantly on the lipid packing defect densities and electrostatic interactions and results in rigidification of the myelin-like model membrane during the early phase of amyloid aggregation. Furthermore, elongation of Aß-40 into higher oligomeric and fibrillar species leads to eventual fluidization of the model membrane followed by extensive lipid membrane tubulation observed in the late phase. Taken together, our results capture mechanistic insights into snapshots of temporal dynamics of Aß-40-myelin-like model membrane interaction and demonstrate how short timescale, local phenomena of binding, and fibril-mediated load generation results in the consequent association of lipids with growing amyloid fibrils.


Subject(s)
Amyloid beta-Peptides , Lipids , Myelin Sheath , Humans , Alzheimer Disease/metabolism , Amyloid/chemistry , Amyloid/metabolism , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/metabolism , Lipids/chemistry , Myelin Sheath/chemistry , Myelin Sheath/metabolism , Peptide Fragments/chemistry , Peptide Fragments/metabolism
6.
EMBO J ; 42(2): e111185, 2023 01 16.
Article in English | MEDLINE | ID: mdl-36416085

ABSTRACT

The misfolding and mutation of Cu/Zn superoxide dismutase (SOD1) is commonly associated with amyotrophic lateral sclerosis (ALS). SOD1 can accumulate within stress granules (SGs), a type of membraneless organelle, which is believed to form via liquid-liquid phase separation (LLPS). Using wild-type, metal-deficient, and different ALS disease mutants of SOD1 and computer simulations, we report here that the absence of Zn leads to structural disorder within two loop regions of SOD1, triggering SOD1 LLPS and amyloid formation. The addition of exogenous Zn to either metal-free SOD1 or to the severe ALS mutation I113T leads to the stabilization of the loops and impairs SOD1 LLPS and aggregation. Moreover, partial Zn-mediated inhibition of LLPS was observed for another severe ALS mutant, G85R, which shows perturbed Zn-binding. By contrast, the ALS mutant G37R, which shows reduced Cu-binding, does not undergo LLPS. In addition, SOD1 condensates induced by Zn-depletion exhibit greater cellular toxicity than aggregates formed by prolonged incubation under aggregating conditions. Overall, our work establishes a role for Zn-dependent modulation of SOD1 conformation and LLPS properties that may contribute to amyloid formation.


Subject(s)
Superoxide Dismutase-1 , Zinc , Humans , Amyotrophic Lateral Sclerosis/enzymology , Mutation , Superoxide Dismutase-1/chemistry , Superoxide Dismutase-1/genetics , Zinc/chemistry , Protein Folding
7.
Int J Biol Macromol ; 217: 492-505, 2022 Sep 30.
Article in English | MEDLINE | ID: mdl-35841961

ABSTRACT

Conventional drug development strategies typically use pocket in protein structures as drug-target sites. They overlook the plausible effects of protein evolvability and resistant mutations on protein structure which in turn may impair protein-drug interaction. In this study, we used an integrated evolution and structure guided strategy to develop potential evolutionary-escape resistant therapeutics using receptor binding domain (RBD) of SARS-CoV-2 spike-protein/S-protein as a model. Deploying an ensemble of sequence space exploratory tools including co-evolutionary analysis and deep mutational scans we provide a quantitative insight into the evolutionarily constrained subspace of the RBD sequence-space. Guided by molecular simulation and structure network analysis we highlight regions inside the RBD, which are critical for providing structural integrity and conformational flexibility. Using fuzzy C-means clustering we combined evolutionary and structural features of RBD and identified a critical region. Subsequently, we used computational drug screening using a library of 1615 small molecules and identified one lead molecule, which is expected to target the identified region, critical for evolvability and structural stability of RBD. This integrated evolution-structure guided strategy to develop evolutionary-escape resistant lead molecules have potential general applications beyond SARS-CoV-2.


Subject(s)
COVID-19 , SARS-CoV-2 , Angiotensin-Converting Enzyme 2 , Binding Sites , Humans , Mutation , Peptidyl-Dipeptidase A/metabolism , Protein Binding , Spike Glycoprotein, Coronavirus/chemistry
8.
Adv Protein Chem Struct Biol ; 128: 79-111, 2022.
Article in English | MEDLINE | ID: mdl-35034727

ABSTRACT

Over the last 25 years, the biology of membrane proteins, including the PFPs-membranes interactions is seeking attention for the development of successful drug molecules against a number of infectious diseases. Pore forming toxins (PFTs), the largest family of PFPs are considered as a group of virulence factors produced in a large number of pathogenic systems which include streptococcus, pneumonia, Staphylococcus aureus, E. coli, Mycobacterium tuberculosis, group A and B streptococci, Corynebacterium diphtheria and many more. PFTs are generally utilized by the disease causing pathogens to disrupt the host first line of defense i.e. host cell membranes through pore formation strategy. Although, pore formation is the principal mode of action of the PFTs but they can have additional adverse effects on the hosts including immune evasion. Recently, structural investigation of different PFTs have imparted the molecular mechanistic insights into how PFTs get transformed from its inactive state to active toxic state. On the basis of their structural entity, PFTs have been classified in different types and their mode of actions alters in terms of pore formation and corresponding cellular toxicity. Although pathogen genome analysis can identify the probable PFTs depending upon their structural diversity, there are so many PFTs which utilize the local environmental conditions to generate their pore forming ability using a novel strategy which is known as "conformational switch" of a protein. This conformational switch is considered as characteristics of the phase shifting proteins which were often utilized by many pathogenic systems to protect them from the invaders through allosteric communication between distant regions of the protein. In this chapter, we discuss the structure function relationships of PFTs and how activity of PFTs varies with the change in the environmental conditions has been explored. Finally, we demonstrate these structural insights to develop therapeutic potential to treat the infections caused by multidrug resistant pathogens.


Subject(s)
Escherichia coli , Virulence Factors , Cell Membrane , Membrane Proteins , Pore Forming Cytotoxic Proteins
9.
J Phys Chem B ; 125(40): 11099-11111, 2021 10 14.
Article in English | MEDLINE | ID: mdl-34473498

ABSTRACT

Loss of function and aggregation of the neuronal protein α-Synuclein (A-Syn) underlies the pathogenesis of Parkinson's disease (PD), and both the function and aggregation of this protein happen to be mediated via its binding to the synaptic vesicles (SVs) at the presynaptic termini. An essential constituent of SV membranes is cholesterol, with which A-Syn directly interacts while binding to membranes. Thus, cholesterol content in SV membranes is likely to affect the binding of A-Syn to these vesicles and consequently its functional and pathogenic behaviors. Interestingly, the dyshomeostasis of cholesterol has often been associated with PD, with reports linking both high and low cholesterol levels to an increased risk of neurodegeneration. Herein, using SV-mimicking liposomes containing increasing percentages of membrane cholesterol, we show (with mathematical interpretation) that the binding of A-Syn to synaptic-like vesicles is strongest in the presence of an optimum cholesterol content, which correlates to its maximum function and minimum aggregation. This implicates a minimum risk of neurodegeneration at optimum cholesterol levels and rationalizes the existing controversial relationship between cholesterol levels and PD. Increased membrane cholesterol was, however, found to protect against damage caused by aggregated A-Syn, complementing previous reports and portraying one advantage of high cholesterol over low.


Subject(s)
Parkinson Disease , alpha-Synuclein , Cholesterol , Humans , Neurons , Synaptic Vesicles
10.
RSC Chem Biol ; 2(2): 592-605, 2021 Apr 01.
Article in English | MEDLINE | ID: mdl-34458802

ABSTRACT

Understanding of prion aggregation in a membrane environment may help to ameliorate neurodegenerative complications caused by the amyloid forms of prions. Here, we investigated the membrane binding-induced aggregation of yeast prion protein Sup35. Using the combination of fluorescence correlation spectroscopy (FCS) at single molecule resolution and other biophysical studies, we establish that lipid composition and lipid/protein ratio are key modulators of the aggregation kinetics of Sup35. In the presence of a zwitterionic membrane (DMPC), Sup35 exhibited novel biphasic aggregation kinetics at lipid/protein ratios ranging between 20 : 1 and 70 : 1 (termed here as the optimum lipid concentration, OLC). In ratios below (low lipid concentration, LLC) and above (ELC, excess lipid concentration) that range, the aggregation was found to be monophasic. In contrast, in the presence of negatively charged membranes, we did not observe any bi-phasic aggregation kinetics in the entire range of protein to lipid ratios. Our results provide a mechanistic description of the role that membrane concentration/composition-modulated aggregation may play in neurodegenerative diseases.

11.
J Phys Chem B ; 125(33): 9402-9416, 2021 08 26.
Article in English | MEDLINE | ID: mdl-34384214

ABSTRACT

ß-Glucosidases are often inhibited by their reaction product glucose and a barrier to the efficient lignocellulosic biomass hydrolysis to glucose. We had previously reported the mutants, C174V, and H229S, with a nearly 2-fold increased glucose tolerance over the wild type (WT), H0HC94, encoded in Agrobacterium tumefaciens 5A (apparent Ki,Glc = 686 mM). We report our steady-state and time-resolved intrinsic fluorescence spectroscopy, circular dichroism, and isothermal titration calorimetry (ITC) studies to further understand increased glucose tolerance. Changes in the mutants' emission intensity and the differential change in quenching rate in the absence and presence of glucose reflect changes in protein conformation by glucose. Time-resolved lifetime and anisotropy measurements further indicated the microenvironment differences across solvent-exposed tryptophan residues and a higher hydrodynamic radius due to glucose binding, respectively. ITC measurements confirmed the increase of glucose binding sites in the mutants. The experiment results were supported by molecular dynamics simulations, which revealed significant variations in the glucose-protein hydrogen-bonding profiles. Protein structure network analysis of the simulated structures further indicates the mutants' conformation change than the WT. Computational studies also indicated additional glucose binding sites in mutants. Our results indicate the role of glucose binding in modulating the enzyme response to glucose.


Subject(s)
Agrobacterium tumefaciens , beta-Glucosidase , Agrobacterium tumefaciens/genetics , Agrobacterium tumefaciens/metabolism , Binding Sites , Glucose , Protein Binding , Protein Conformation , Spectrometry, Fluorescence , Substrate Specificity
12.
Commun Biol ; 4(1): 518, 2021 05 03.
Article in English | MEDLINE | ID: mdl-33941845

ABSTRACT

The fibrillation pathway of alpha-Synuclein, the causative protein of Parkinson's disease, encompasses transient, heterogeneous oligomeric forms whose structural understanding and link to toxicity are not yet understood. We report that the addition of the physiologically-available small molecule heme at a sub-stoichiometric ratio to either monomeric or aggregated α-Syn, targets a His50 residue critical for fibril-formation and stabilizes the structurally-heterogeneous populations of aggregates into a minimally-toxic oligomeric state. Cryo-EM 3D reconstruction revealed a 'mace'-shaped structure of this monodisperse population of oligomers, which is comparable to a solid-state NMR Greek key-like motif (where the core residues are arranged in parallel in-register sheets with a Greek key topology at the C terminus) that forms the fundamental unit/kernel of protofilaments. Further structural analyses suggest that heme binding induces a distortion in the Greek key-like architecture of the mace oligomers, which impairs their further appending into protofilaments and fibrils. Additionally, our study reports a novel mechanism of prevention as well as reclamation of amyloid fibril formation by blocking an inter-protofilament His50 residue using a small molecule.


Subject(s)
Amyloid/chemistry , Heme/metabolism , Neuroblastoma/pathology , Protein Multimerization , alpha-Synuclein/chemistry , alpha-Synuclein/metabolism , Heme/chemistry , Humans , Neuroblastoma/metabolism , Protein Conformation , Tumor Cells, Cultured
13.
Elife ; 102021 04 07.
Article in English | MEDLINE | ID: mdl-33825682

ABSTRACT

Aggregation of Cu-Zn superoxide dismutase (SOD1) is implicated in the motor neuron disease, amyotrophic lateral sclerosis (ALS). Although more than 140 disease mutations of SOD1 are available, their stability or aggregation behaviors in membrane environment are not correlated with disease pathophysiology. Here, we use multiple mutational variants of SOD1 to show that the absence of Zn, and not Cu, significantly impacts membrane attachment of SOD1 through two loop regions facilitating aggregation driven by lipid-induced conformational changes. These loop regions influence both the primary (through Cu intake) and the gain of function (through aggregation) of SOD1 presumably through a shared conformational landscape. Combining experimental and theoretical frameworks using representative ALS disease mutants, we develop a 'co-factor derived membrane association model' wherein mutational stress closer to the Zn (but not to the Cu) pocket is responsible for membrane association-mediated toxic aggregation and survival time scale after ALS diagnosis.


Amyotrophic lateral sclerosis, or ALS, is an incurable neurodegenerative disease in which a person slowly loses specialized nerve cells that control voluntary movement. It is not fully understood what causes this fatal disease. However, it is suspected that clumps, or aggregates, of a protein called SOD1 in nerve cells may play a crucial role. More than 140 mutations in the gene for SOD1 have been linked to ALS, with varying degrees of severity. But it is still unclear how these mutations cause SOD1 aggregation or how different mutations influence the survival rate of the disease. The protein SOD1 contains a copper ion and a zinc ion, and it is possible that mutations that affect how these two ions bind to SOD1 influences the severity of the disease. To investigate this, Sannigrahi, Chowdhury, Das et al. genetically engineered mutants of the SOD1 protein which each contain only one metal ion. Experiments on these mutated proteins showed that the copper ion is responsible for the protein's role in neutralizing harmful reactive molecules, while the zinc ion stabilizes the protein against aggregation. Sannigrahi et al. found that when the zinc ion was removed, the SOD1 protein attached to a structure inside the cell called the mitochondria and formed toxic aggregates. Sannigrahi et al. then used these observations to build a computational model that incorporated different mutations that have been previously associated with ALS. The model suggests that mutations close to the site where zinc binds to the SOD1 protein increase disease severity and shorten survival time after diagnosis. This model was then experimentally validated using two disease variants of ALS that have mutations close to the sites where zinc or copper binds. These findings still need to be tested in animals and humans to see if these mechanisms hold true in a multicellular organism. This discovery could help design new ALS treatments that target the zinc binding site on SOD1 or disrupt the protein's interactions with the mitochondria.


Subject(s)
Amyotrophic Lateral Sclerosis/enzymology , Cell Membrane/enzymology , Neurons/enzymology , Superoxide Dismutase-1/metabolism , Zinc/metabolism , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/pathology , Binding Sites , Cell Line, Tumor , Cell Membrane/pathology , Copper/metabolism , Humans , Kinetics , Models, Molecular , Mutagenesis, Site-Directed , Mutation , Neurons/pathology , Protein Aggregates , Protein Aggregation, Pathological , Protein Binding , Protein Conformation , Protein Folding , Structure-Activity Relationship , Superoxide Dismutase-1/genetics
15.
ACS Chem Neurosci ; 11(20): 3442-3454, 2020 10 21.
Article in English | MEDLINE | ID: mdl-33044818

ABSTRACT

Parkinson's disease (PD) is the second most common neurodegenerative disorder, the pathogenesis of which is closely linked to the misfolding and aggregation of the neuronal protein α-Synuclein (A-Syn). Numerous molecules that inhibit/modulate the pathogenic aggregation of A-Syn in an effort to tackle PD pathogenesis have been reported, but none so far have been successful in treating the disease at the clinic. One major reason for this is the poor blood-brain barrier (BBB) permeability of most of the molecules being used. Therefore, using BBB-permeable (and biocompatible) nanomaterials as fibrillation modulators is gaining importance. In the present work, we show how nontoxic and ultrasmall gold nanoclusters (AuNCs) can systematically modulate the pathogenic fibrillation of A-Syn in vitro, based on the chemical nature of their capping agents, using two reported easily synthesizable AuNCs as models. In addition, we detect the BBB permeability in mice of one of these AuNCs solely by making use of its intrinsic fluorescence. Thus, our work exemplifies how AuNCs can be potential therapeutics against PD; while also acting as fluorescent probes for their own BBB permeability.


Subject(s)
Parkinson Disease , alpha-Synuclein , Animals , Blood-Brain Barrier/metabolism , Gold , Mice , Neurons/metabolism , alpha-Synuclein/metabolism
16.
ACS Chem Neurosci ; 11(18): 2789-2792, 2020 09 16.
Article in English | MEDLINE | ID: mdl-32880441

ABSTRACT

The recent outbreak of Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) from Wuhan, China, was caused by a single-stranded RNA virus which has kept the entire world stranded. The outbreak was first diagnosed with respiratory illness, but recent findings of acute necrotizing hemorrhage of brain, brain encephalopathy, and the presence of the virus in the cerebrospinal fluid (CSF) have unveiled its neuroinvasivness. Various clinical features related to the central nervous system (CNS) and peripheral nervous system (PNS) due to COVID-19 infection are now identified. We demonstrate here an apparent similarity in neurological disorders of COVID-19 with CNS tuberculosis, which suggests that some anti-tubercular drugs may be used as therapeutic agents against COVID-19 infection.


Subject(s)
Central Nervous System Diseases/virology , Coronavirus Infections/complications , Pneumonia, Viral/complications , Tuberculosis, Central Nervous System , Animals , Betacoronavirus , Brain/virology , COVID-19 , Humans , Pandemics , SARS-CoV-2 , Tuberculosis, Central Nervous System/immunology , Tuberculosis, Central Nervous System/pathology , Tuberculosis, Central Nervous System/physiopathology
17.
ACS Omega ; 5(27): 16395-16405, 2020 Jul 14.
Article in English | MEDLINE | ID: mdl-32685802

ABSTRACT

We report here the preparation of an aminoxy amide-based pseudopeptide-derived building block using furanoid sugar molecules. Through the cyclo-oligomerization reaction, we generate a hybrid triazole/aminoxy amide macrocycle using the as-prepared building block. The novel conformation of the macrocycle has been characterized using NMR and molecular modeling studies, which show a strong resemblance of our synthesized compound to d-,l-α-aminoxy acid-based cyclic peptides that contain uniform backbone chirality. We observe that the macrocycle can efficiently and selectively bind Cl- ion and transport Cl- ion across a lipid bilayer. 1H NMR anion binding studies suggest a coherent relationship between the acidity of aminoxy amide N-H and triazole C-H proton binding strength. Using time-based fluorescence assay, we show that the macrocycle acts as a mobile transporter and follows an antiport mechanism. Our synthesized macrocycle imposes cancer cell death by disrupting ionic homeostasis through Cl- ion transport. The macrocycle induced cytochrome c leakage and changes in mitochondrial membrane potential along with activation of family of caspases, suggesting that the cellular apoptosis occurs through a caspase-dependent intrinsic pathway. The present results suggest the possibility of using the macrocycle as a biological tool of high therapeutic value.

18.
Commun Biol ; 3(1): 382, 2020 07 15.
Article in English | MEDLINE | ID: mdl-32669705

ABSTRACT

It is now established that a protein can switch between multiple conformations to enable altered functions. Several pathogens including SARS COV2 utilize context-dependent conformational switches of particular proteins to invade host membrane to establish infections. In this perspective, we first discuss the understanding of the conformational switch of a protein towards the productive infections as a dark side of nature. Next, the unexplored binary combination of the sequences of SARS COV2 spike protein and the similarity with diverse pathogen derived proteins have been discussed to obtain novel molecular insights into the process of infection.


Subject(s)
COVID-19/virology , SARS-CoV-2/physiology , Viral Proteins/metabolism , Antiviral Agents/therapeutic use , Cell Membrane/metabolism , Cell Membrane/virology , Drug Design , Humans , Infections , Protein Conformation , Viral Proteins/chemistry , COVID-19 Drug Treatment
19.
ACS Chem Neurosci ; 11(11): 1610-1619, 2020 06 03.
Article in English | MEDLINE | ID: mdl-32407096

ABSTRACT

The accumulation of an inherently disordered protein α-synuclein (α-syn) aggregates in brain tissue play a pivotal role in the pathology and etiology of Parkinson's disease. Aggregation of α-syn has been found to be complex and heterogeneous, occurring through multitudes of early- and late-stage intermediates. Because of the inherent complexity and large dynamic range (between a few microseconds to several days under in vitro measurement conditions), it is difficult for the conventional biophysical and biochemical techniques to sample the entire time window of α-syn aggregation. Here, for the first time, we introduced the Z-scan technique as a novel tool to investigate different conformations formed in the early and late stage of temperature and mechanical stress-induced α-syn aggregation, in which different species showed its characteristic nonlinear characteristics. A power-dependent study was also performed to observe the changes in the protein nonlinearity. The perceived nonlinearity was accredited to the thermal-lensing effect. A switch in the sign of the refractive nonlinearity was observed for the first time as a signature of the late oligomeric conformation, a prime suspect that triggers cell death associated with neurodegeneration. We validate Z-scan results using a combination of different techniques, like thioflavin-T fluorescence assay, fluorescence correlation spectroscopy, Fourier-transform infrared spectroscopy, and atomic force microscopy. We believe that this simple, inexpensive, and sensitive method can have potential future applications in detecting/monitoring conformations in other essential peptides/proteins related to different neurodegenerative and other human diseases.


Subject(s)
Parkinson Disease , alpha-Synuclein , Brain/metabolism , Humans , alpha-Synuclein/metabolism
20.
Langmuir ; 36(13): 3522-3530, 2020 04 07.
Article in English | MEDLINE | ID: mdl-32160748

ABSTRACT

Kinetoplastid membrane protein-11 (KMP-11), expressed in all stages of leishmanial life cycle, is considered a potential candidate for leishmaniasis vaccine. KMP-11 is found on the membrane surface of the parasite. Although the biological function of KMP-11 is unknown, we hypothesize from its sequence analysis that it may interact with the macrophage membrane and may influence the entry process of the parasite into the host cell. To validate this hypothesis, we have investigated the interaction of KMP-11 with unilamellar anionic phospholipid vesicles and explored its pore-forming activity. The decrease in negative ζ-potential of the vesicles and reduction in the fluorescence intensity of membrane-bound dye DiI C-18 suggest a strong association of KMP-11 with the membrane. The fluorescence leakage experiment as well as phase contrast microscopy shows direct evidence of KMP-11-induced pore formation in an anionic membrane. Incorporation of cholesterol into the membrane has been found to inhibit pore formation induced by KMP-11, suggesting an important role of cholesterol in leishmaniasis. Interestingly, vesicles containing only neutral phospholipid do not exhibit any tendency toward pore formation.


Subject(s)
Cholesterol , Membrane Proteins , Phospholipids , Leishmania , Membranes , Protozoan Proteins
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