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1.
Int J Biol Macromol ; 272(Pt 1): 132738, 2024 Jun.
Article En | MEDLINE | ID: mdl-38825269

Piperine (PIP) has been known for its pharmacological activities with low water solubility and poor dissolution, which limits its nutritional application. The purpose of this research was to enhance PIP stability, dispersibility and biological activity by preparing PIP nanoparticles using the wet-media milling approach combined with nanosuspension solidification methods of spray/freeze drying. Octenyl succinic anhydride (OSA)-modified waxy maize starch was applied as the stabilizer to suppress aggregation of PIP nanoparticles. The particle size, redispersibility, storage stability and in vitro release behavior of PIP nanoparticles were measured. The regulating effect on adipocyte differentiation was evaluated using 3T3-L1 cell model. Results showed that PIP nanoparticles had a reduced particle size of 60 ± 1 nm, increased release rate in the simulated gastric (SGF) and intestinal fluids (SIF) and enhanced inhibition effect on adipogenesis in 3T3-L1 cells compared with free PIP, indicating that PIP-loaded nanoparticles with improved stability and anti-adipogenic property were developed successfully by combining wet-media milling and drying methods.


3T3-L1 Cells , Adipocytes , Adipogenesis , Alkaloids , Benzodioxoles , Nanoparticles , Piperidines , Polyunsaturated Alkamides , Starch , Animals , Mice , Nanoparticles/chemistry , Polyunsaturated Alkamides/chemistry , Polyunsaturated Alkamides/pharmacology , Benzodioxoles/pharmacology , Benzodioxoles/chemistry , Piperidines/pharmacology , Piperidines/chemistry , Adipogenesis/drug effects , Alkaloids/chemistry , Alkaloids/pharmacology , Adipocytes/drug effects , Starch/chemistry , Starch/analogs & derivatives , Particle Size , Drug Liberation , Cell Differentiation/drug effects
2.
Molecules ; 29(10)2024 May 20.
Article En | MEDLINE | ID: mdl-38792267

In this article, we introduce a proof-of-concept strategy, Computational Predictive and Electrochemical Detection of Metabolites (CP-EDM), to expedite the discovery of drug metabolites. The use of a bioactive natural product, piperine, that has a well-curated metabolite profile but an unpredictable computational metabolism (Biotransformer v3.0) was selected. We developed an electrochemical reaction to oxidize piperine into a range of metabolites, which were detected by LC-MS. A series of chemically plausible metabolites were predicted based on ion fragmentation patterns. These metabolites were docked into the active site of CYP3A4 using Autodock4.2. From the clustered low-energy profile of piperine in the active site, it can be inferred that the most likely metabolic position of piperine (based on intermolecular distances to the Fe-oxo active site) is the benzo[d][1,3]dioxole motif. The metabolic profile was confirmed by comparison with the literature, and the electrochemical reaction delivered plausible metabolites, vide infra, thus, demonstrating the power of the hyphenated technique of tandem electrochemical detection and computational evaluation of binding poses. Taken together, we outline a novel approach where diverse data sources are combined to predict and confirm a metabolic outcome for a bioactive structure.


Alkaloids , Benzodioxoles , Electrochemical Techniques , Piperidines , Polyunsaturated Alkamides , Benzodioxoles/chemistry , Benzodioxoles/metabolism , Polyunsaturated Alkamides/metabolism , Polyunsaturated Alkamides/chemistry , Piperidines/chemistry , Piperidines/metabolism , Alkaloids/metabolism , Alkaloids/chemistry , Electrochemical Techniques/methods , Molecular Docking Simulation , Humans , Chromatography, Liquid/methods
3.
Int J Mol Sci ; 25(8)2024 Apr 22.
Article En | MEDLINE | ID: mdl-38674150

Saracatinib (AZD0530) is a dual Src/Abl inhibitor initially developed by AstraZeneca for cancer treatment; however, data from 2006 to 2024 reveal that this drug has been tested not only for cancer treatment, but also for the treatment of other diseases. Despite the promising pre-clinical results and the tolerability shown in phase I trials, where a maximum tolerated dose of 175 mg was defined, phase II clinical data demonstrated a low therapeutic action against several cancers and an elevated rate of adverse effects. Recently, pre-clinical research aimed at reducing the toxic effects and enhancing the therapeutic performance of saracatinib using nanoparticles and different pharmacological combinations has shown promising results. Concomitantly, saracatinib was repurposed to treat Alzheimer's disease, targeting Fyn. It showed great clinical results and required a lower daily dose than that defined for cancer treatment, 125 mg and 175 mg, respectively. In addition to Alzheimer's disease, this Src inhibitor has also been studied in relation to other health conditions such as pulmonary and liver fibrosis and even for analgesic and anti-allergic functions. Although saracatinib is still not approved by the Food and Drug Administration (FDA), the large number of alternative uses for saracatinib and the elevated number of pre-clinical and clinical trials performed suggest the huge potential of this drug for the treatment of different kinds of diseases.


Benzodioxoles , Drug Repositioning , Quinazolines , Humans , Drug Repositioning/methods , Quinazolines/therapeutic use , Quinazolines/chemistry , Quinazolines/pharmacology , Benzodioxoles/therapeutic use , Benzodioxoles/chemistry , Benzodioxoles/pharmacology , Animals , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/adverse effects , Alzheimer Disease/drug therapy , src-Family Kinases/antagonists & inhibitors , src-Family Kinases/metabolism , Neoplasms/drug therapy , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/chemistry
4.
Int J Biol Macromol ; 268(Pt 1): 131777, 2024 May.
Article En | MEDLINE | ID: mdl-38663710

In this study, a new carrier for loading piperine was prepared using pepper starch, and its interaction mechanism was investigated. The porous pepper starch-piperine complex (PPS-PIP) showed higher loading efficiency (76.15 %) compared to the porous corn starch-piperine complex (PCS-PIP (52.34 %)). This may be ascribed to the hemispherical shell structure of porous pepper starch (PPS) compared to the porous structure of porous corn starch (PCS) based on the SEM result. PPS-PIP had smaller particle size (10.53 µm), higher relative crystallinity (38.95 %), and better thermal stability (87.45 °C) than PCS-PIP (17.37 µm, 32.17 %, 74.35 °C). Fourier transform infrared spectroscopy (FTIR) results implied that piperine not only forms a complex with amylose but may also be physically present in porous starch. This was demonstrated by the short-range order and X-ray type. Molecular dynamics simulations confirmed that hydrogen bonding is the primary interaction between amylose and piperine. Besides the formation of the amylose-piperine complex, some of the piperine is also present in physical form.


Alkaloids , Benzodioxoles , Piperidines , Polyunsaturated Alkamides , Starch , Piperidines/chemistry , Benzodioxoles/chemistry , Alkaloids/chemistry , Starch/chemistry , Polyunsaturated Alkamides/chemistry , Porosity , Amylose/chemistry , Molecular Dynamics Simulation , Hydrogen Bonding , Particle Size , Spectroscopy, Fourier Transform Infrared , Capsicum/chemistry
5.
J Biomater Sci Polym Ed ; 35(8): 1177-1196, 2024 06.
Article En | MEDLINE | ID: mdl-38436277

This research aims to develop the formulation of Dissolving Microneedle Piperine (DMNs PIP) and evaluate the effect of polymer concentration on characterisation and permeation testing results in ex vivo. DMNs PIP were prepared from varying concentrations of piperine (PIP) (10, 15, and 20% w/w) and polymers of polyvinyl alcohol (PVA): Polyvinyl pyrrolidone (30:60 and 60:25), respectively. Then the morphological evaluation of the formula was carried out, followed by mechanical strength testing. Furthermore, the density, LOD, and weight percentage of piperine in the dried microneedle were calculated and the determination of volume, needle weight and piperine weight and analysed. Ex vivo testing, X-Ray Diffraction, FTIR and hemolysis tests were carried out. PIP with PVA and PVP (F1) polymers produced DMN with mechanical strength (8.35 ± 0.11%) and good penetration ability. In vitro tests showed that the F1 polymer mixture gave good penetration (95.02 ± 1.42 µg/cm2), significantly higher than the F2, F3, F4, and F5 polymer mixtures. The DMNs PIP characterisation results through XRD analysis showed a distinctive peak in the 20-30 region, indicating the presence of crystals. The FTIR study showed that the characteristics of piperine found in DMNs PIP indicated that piperine did not undergo interactions with polymers. The results of the ex vivo study through DMNs PIP hemolytic testing showed no hemolysis occurred, with the hemolysis index below the 5% threshold reported in the literature. These findings indicate that DMNs PIP is non-toxic and safe to use as alternative for treating inflammation.


Administration, Cutaneous , Alkaloids , Benzodioxoles , Needles , Piperidines , Polyunsaturated Alkamides , Polyvinyl Alcohol , Benzodioxoles/administration & dosage , Benzodioxoles/chemistry , Benzodioxoles/pharmacology , Polyunsaturated Alkamides/chemistry , Polyunsaturated Alkamides/pharmacology , Polyunsaturated Alkamides/administration & dosage , Polyunsaturated Alkamides/pharmacokinetics , Piperidines/chemistry , Piperidines/administration & dosage , Piperidines/pharmacology , Piperidines/pharmacokinetics , Alkaloids/chemistry , Alkaloids/administration & dosage , Alkaloids/pharmacology , Animals , Polyvinyl Alcohol/chemistry , Hemolysis/drug effects , Povidone/chemistry , Drug Delivery Systems , Solubility , Skin/metabolism , Skin/drug effects , Skin Absorption
6.
J Pharm Sci ; 113(7): 1874-1884, 2024 Jul.
Article En | MEDLINE | ID: mdl-38354909

Intermolecular interactions between drug and co-former are crucial in the formation, release and physical stability of co-amorphous system. However, the interactions remain difficult to investigate with only experimental tools. In this study, intermolecular interactions of co-amorphous curcumin-piperine (i.e., CUR-PIP CM) during formation, dissolution and storage were explored by integrating experimental and modeling techniques. The formed CUR-PIP CM exhibited the strong hydrogen bond interaction between the phenolic OH group of CUR and the CO group of PIP as confirmed by FTIR, ss 13C NMR and molecular dynamics (MD) simulation. In comparison to crystalline CUR, crystalline PIP and their physical mixture, CUR-PIP CM performed significantly increased dissolution accompanied by the synchronized release of CUR and PIP, which arose from the greater interaction energy of H2O-CUR molecules and H2O-PIP molecules than CUR-PIP molecules, breaking the hydrogen bond between CUR and PIP molecules, and then causing a pair-wise solvation of CUR-PIP CM at the molecular level. Furthermore, the stronger intermolecular interaction between CUR and PIP was revealed by higher binding energy of CUR-PIP molecules, which contributed to the excellent physical stability of CUR-PIP CM over amorphous CUR or PIP. The study provides a unique insight into the formation, release and stability of co-amorphous system from MD perspective. Meanwhile, this integrated technique can be used as a practical methodology for the future design of co-amorphous formulations.


Benzodioxoles , Curcumin , Drug Stability , Hydrogen Bonding , Molecular Dynamics Simulation , Piperidines , Polyunsaturated Alkamides , Solubility , Curcumin/chemistry , Piperidines/chemistry , Polyunsaturated Alkamides/chemistry , Benzodioxoles/chemistry , Drug Liberation , Crystallization/methods , Spectroscopy, Fourier Transform Infrared/methods , Chemistry, Pharmaceutical/methods , Magnetic Resonance Spectroscopy/methods , Alkaloids
7.
Curr Top Med Chem ; 24(9): 797-809, 2024.
Article En | MEDLINE | ID: mdl-38141184

Sesamol, one of the key bioactive ingredients of sesame seeds (Sesamum indicum L.), is responsible for many of its possible nutritional benefits. Both the Chinese and Indian medical systems have recognized the therapeutic potential of sesame seeds. It has been shown to have significant therapeutic potential against oxidative stress, inflammatory diseases, metabolic syndrome, neurodegeneration, and mental disorders. Sesamol is a benign molecule that inhibits the expression of inflammatory indicators like numerous enzymes responsible for inducing inflammation, protein kinases, cytokines, and redox status. This review summarises the potential beneficial effects of sesamol against neurological diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Recently, sesamol has been shown to reduce amyloid peptide accumulation and attenuate cognitive deficits in AD models. Sesamol has also been demonstrated to reduce the severity of PD and HD in animal models by decreasing oxidative stress and inflammatory pathways. The mechanism of sesamol's pharmacological activities against neurodegenerative diseases will also be discussed in this review.


Benzodioxoles , Neurodegenerative Diseases , Phenols , Humans , Benzodioxoles/pharmacology , Benzodioxoles/chemistry , Benzodioxoles/therapeutic use , Phenols/pharmacology , Phenols/chemistry , Neurodegenerative Diseases/drug therapy , Animals , Oxidative Stress/drug effects , Antioxidants/pharmacology , Antioxidants/chemistry , Neuroprotective Agents/pharmacology , Neuroprotective Agents/chemistry
8.
Molecules ; 28(14)2023 Jul 22.
Article En | MEDLINE | ID: mdl-37513459

Gastric cancer is one of the most frequent types of neoplasms worldwide, usually presenting as aggressive and difficult-to-manage tumors. The search for new structures with anticancer potential encompasses a vast research field in which natural products arise as promising alternatives. In this scenario, piperine, an alkaloid of the Piper species, has received attention due to its biological activity, including anticancer attributes. The present work proposes three heating-independent, reliable, low-cost, and selective methods for obtaining piperine from Piper nigrum L. (Black pepper). Electronic (SEM) and optical microscopies, X-ray diffraction, nuclear magnetic resonance spectroscopies (13C and 1H NMR), and optical spectroscopies (UV-Vis, photoluminescence, and FTIR) confirm the obtention of piperine crystals. The MTT assay reveals that the piperine samples exhibit good cytotoxic activity against primary and metastasis models of gastric cancer cell lines from the Brazilian Amazon. The samples showed selective cytotoxicity on the evaluated models, revealing higher effectiveness in cells bearing a higher degree of aggressiveness. Moreover, the investigated piperine crystals demonstrated the ability to act as a good cytotoxicity enhancer when combined with traditional chemotherapeutics (5-FU and GEM), allowing the drugs to achieve the same cytotoxic effect in cells employing lower concentrations. These results establish piperine as a promising molecule for therapy investigations in aggressive gastric cancer, both in its isolated form or as a bioenhancer.


Alkaloids , Antineoplastic Agents , Piper nigrum , Stomach Neoplasms , Humans , Stomach Neoplasms/drug therapy , Alkaloids/chemistry , Benzodioxoles/chemistry , Piperidines/chemistry , Polyunsaturated Alkamides/chemistry , Piper nigrum/chemistry , Antineoplastic Agents/pharmacology
9.
Biomed Pharmacother ; 165: 115107, 2023 Sep.
Article En | MEDLINE | ID: mdl-37423171

The antitumor effects of traditional drugs have received increasing attention and active antitumor components extracted from traditional drugs have shown good efficacy with minimal adverse events. Cepharanthine(CEP for short) is an active component derived from the Stephania plants of Menispermaceae, which can regulate multiple signaling pathways alone or in combination with other therapeutic drugs to inhibit tumor cell proliferation, induce apoptosis, regulate autophagy, and inhibit angiogenesis, thereby inhibiting tumor progression. Therefore, we retrieved studies concerning CEP's antitumor effects in recent years and summarized the antitumor mechanism and targets, in order to gain new insights and establish a theoretical basis for further development and application of CEP.


Antineoplastic Agents , Benzodioxoles , Benzylisoquinolines , Benzylisoquinolines/chemistry , Benzylisoquinolines/pharmacology , Benzodioxoles/chemistry , Benzodioxoles/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Humans , Cell Line, Tumor , Apoptosis/drug effects , Radiation Tolerance/drug effects , Autophagy/drug effects , Angiogenesis/drug effects
10.
Methods ; 214: 18-27, 2023 06.
Article En | MEDLINE | ID: mdl-37037308

Small molecules that bind to oligomeric protein species such as membrane proteins and fibrils are of clinical interest for development of therapeutics and diagnostics. Definition of the binding site at atomic resolution via NMR is often challenging due to low binding stoichiometry of the small molecule. For fibrils and aggregation intermediates grown in the presence of lipids, we report atomic-resolution contacts to the small molecule at sub nm distance via solid-state NMR using dynamic nuclear polarization (DNP) and orthogonally labelled samples of the protein and the small molecule. We apply this approach to α-synuclein (αS) aggregates in complex with the small molecule anle138b, which is a clinical drug candidate for disease modifying therapy. The small central pyrazole moiety of anle138b is detected in close proximity to the protein backbone and differences in the contacts between fibrils and early intermediates are observed. For intermediate species, the 100 K condition for DNP helps to preserve the aggregation state, while for both fibrils and oligomers, the DNP enhancement is essential to obtain sufficient sensitivity.


Pyrazoles , alpha-Synuclein , alpha-Synuclein/chemistry , alpha-Synuclein/metabolism , Pyrazoles/chemistry , Benzodioxoles/chemistry , Magnetic Resonance Spectroscopy , Protein Aggregates
11.
Molecules ; 28(5)2023 Feb 24.
Article En | MEDLINE | ID: mdl-36903367

Synthetic cathinones, such as 3,4-methylenedioxypyrovalerone (MDPV), are widely abused due to their psychostimulant effects. As they are chiral molecules, studies of their stereochemical stability (racemization can occur in certain temperatures and acidic/basic environments) and of their biological and/or toxicity effects (enantiomers might display different properties) are of great relevance. In this study, the liquid chromatography (LC) semi-preparative enantioresolution of MDPV was optimized to collect both enantiomers with high recovery rates and enantiomeric ratio (e.r.) values. The absolute configuration of the MDPV enantiomers was determined by electronic circular dichroism (ECD) with the aid of theoretical calculations. The first eluted enantiomer was identified as S-(-)-MDPV and the second eluted enantiomer was identified as R-(+)-MDPV. A racemization study was performed by LC-UV, showing enantiomers' stability up to 48 h at room temperature and 24 h at 37 °C. Racemization was only affected by higher temperatures. The potential enantioselectivity of MDPV in cytotoxicity and in the expression of neuroplasticity-involved proteins-brain-derived neurotrophic factor (BDNF) and cyclin-dependent kinase 5 (Cdk5)-was also evaluated using SH-SY5Y neuroblastoma cells. No enantioselectivity was observed.


Central Nervous System Stimulants , Neuroblastoma , Humans , Synthetic Cathinone , Stereoisomerism , Chromatography, Liquid , Pyrrolidines/chemistry , Benzodioxoles/chemistry
12.
Crit Rev Food Sci Nutr ; 63(16): 2840-2850, 2023.
Article En | MEDLINE | ID: mdl-34609267

Brain aging is one of the unavoidable aspects of geriatric life. As one ages, changes such as the shrinking of certain parts (particularly the frontal cortex, which is vital to learning and other complex mental activities) of the brain may occur. Consequently, communications between neurons are less effective, and blood flow to the brain could also decrease. Efforts made at the biological level for repair become inadequate, leading to the accumulation of ß-amyloid peptide in the brain faster than its probable degradation mechanism, resulting in cognitive malfunction. Subsequent clinical usage of drugs in battling related brain-aging ailments has been associated with several undesirable side effects. However, recent research has investigated the potential use of natural compounds from food in combating such occurrences. This review provides information about the use of Piper guineense (black pepper) as a possible agent in managing brain aging because of its implications for practical brain function. P. guineense contains an alkaloid (piperine) reported to be an antioxidant, anti-depressant, and central nervous system stimulant. This alkaloid and other related compounds are neuroprotective agents that reduce lipid oxidation and inhibit tangles in the brain tissues.


Alkaloids , Piper nigrum , Piper , Piper nigrum/chemistry , Piper/chemistry , Benzodioxoles/chemistry , Benzodioxoles/pharmacology , Polyunsaturated Alkamides/chemistry , Polyunsaturated Alkamides/pharmacology , Brain
13.
Mini Rev Med Chem ; 23(8): 917-940, 2023.
Article En | MEDLINE | ID: mdl-35894471

Natural products are an invaluable source for the discovery of drug and pesticide candidates. Piperine, a simple and pungent alkaloid, is isolated from several plants of Piperaceae. Piperine and its derivatives displayed a wide range of biological properties, such as antitumor activity, anti-inflammatory activity, antioxidant activity, neuroprotective activity, insecticidal activity, etc. In recent years, lots of works focused on the biological activities, mechanisms of action, total synthesis, and structural modifications of piperine and its derivatives have been conducted. To the best of our knowledge, however, few review articles related to the biological activities, mechanisms of action, total synthesis, and structural modifications of piperine and its derivatives have been reported to date. Therefore, this review summarizes the research advances (from 2014 to 2020) of piperine and its derivatives regarding bioactivity, mechanisms of action, total synthesis, and structural modifications. Meanwhile, the structure-activity relationships of piperine and its derivatives are also discussed.


Alkaloids , Structure-Activity Relationship , Alkaloids/chemistry , Benzodioxoles/pharmacology , Benzodioxoles/chemistry , Piperidines/pharmacology , Piperidines/chemistry , Polyunsaturated Alkamides/pharmacology , Polyunsaturated Alkamides/chemistry
14.
Biochim Biophys Acta Biomembr ; 1865(1): 184078, 2023 01 01.
Article En | MEDLINE | ID: mdl-36279907

Cystic fibrosis (CF) is caused by mutations in the gene that codes for the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR). Recent advances in CF treatment have included use of small-molecule drugs known as modulators, such as Lumacaftor (VX-809), but their detailed mechanism of action and interplay with the surrounding lipid membranes, including cholesterol, remain largely unknown. To examine these phenomena and guide future modulator development, we prepared a set of wild type (WT) and mutant helical hairpin constructs consisting of CFTR transmembrane (TM) segments 3 and 4 and the intervening extracellular loop (termed TM3/4 hairpins) that represent minimal membrane protein tertiary folding units. These hairpin variants, including CF-phenotypic loop mutants E217G and Q220R, and membrane-buried mutant V232D, were reconstituted into large unilamellar phosphatidylcholine (POPC) vesicles, and into corresponding vesicles containing 70 mol% POPC +30 mol% cholesterol, and studied by single-molecule FRET and circular dichroism experiments. We found that the presence of 30 mol% cholesterol induced an increase in helicity of all TM3/4 hairpins, suggesting an increase in bilayer cross-section and hence an increase in the depth of membrane insertion compared to pure POPC vesicles. Importantly, when we added the corrector VX-809, regardless of the presence or absence of cholesterol, all mutants displayed folding and helicity largely indistinguishable from the WT hairpin. Fluorescence spectroscopy measurements suggest that the corrector alters lipid packing and water accessibility. We propose a model whereby VX-809 shields the protein from the lipid environment in a mutant-independent manner such that the WT scaffold prevails. Such 'normalization' to WT conformation is consistent with the action of VX-809 as a protein-folding chaperone.


Cystic Fibrosis Transmembrane Conductance Regulator , Cystic Fibrosis , Humans , Cystic Fibrosis Transmembrane Conductance Regulator/chemistry , Benzodioxoles/pharmacology , Benzodioxoles/chemistry , Benzodioxoles/therapeutic use , Cystic Fibrosis/drug therapy , Cystic Fibrosis/genetics , Cystic Fibrosis/metabolism , Cholesterol , Lipids
15.
Nat Commun ; 13(1): 5385, 2022 09 14.
Article En | MEDLINE | ID: mdl-36104315

Aggregation of amyloidogenic proteins is a characteristic of multiple neurodegenerative diseases. Atomic resolution of small molecule binding to such pathological protein aggregates is of interest for the development of therapeutics and diagnostics. Here we investigate the interaction between α-synuclein fibrils and anle138b, a clinical drug candidate for disease modifying therapy in neurodegeneration and a promising scaffold for positron emission tomography tracer design. We used nuclear magnetic resonance spectroscopy and the cryogenic electron microscopy structure of α-synuclein fibrils grown in the presence of lipids to locate anle138b within a cavity formed between two ß-strands. We explored and quantified multiple binding modes of the compound in detail using molecular dynamics simulations. Our results reveal stable polar interactions between anle138b and backbone moieties inside the tubular cavity of the fibrils. Such cavities are common in other fibril structures as well.


Benzodioxoles , alpha-Synuclein , Benzodioxoles/chemistry , Protein Aggregates , Pyrazoles/chemistry , alpha-Synuclein/metabolism
16.
Int J Mol Sci ; 23(14)2022 Jul 20.
Article En | MEDLINE | ID: mdl-35887341

Herein, we elucidate the biophysical aspects of the interaction of an important protein, Interleukin-6 (IL6), which is involved in cytokine storm syndrome, with a natural product with anti-inflammatory activity, piperine. Despite the role of piperine in the inhibition of the transcriptional protein NF-κB pathway responsible for activation of IL6 gene expression, there are no studies to the best of our knowledge regarding the characterisation of the molecular interaction of the IL6-piperine complex. In this context, the characterisation was performed with spectroscopic experiments aided by molecular modelling. Fluorescence spectroscopy alongside van't Hoff analyses showed that the complexation event is a spontaneous process driven by non-specific interactions. Circular dichroism aided by molecular dynamics revealed that piperine caused local α-helix reduction. Molecular docking and molecular dynamics disclosed the microenvironment of interaction as non-polar amino acid residues. Although piperine has three available hydrogen bond acceptors, only one hydrogen-bond was formed during our simulation experiments, reinforcing the major role of non-specific interactions that we observed experimentally. Root mean square deviation (RMSD) and hydrodynamic radii revealed that the IL6-piperine complex was stable during 800 ns of simulation. Taken together, these results can support ongoing IL6 drug discovery efforts.


Interleukin-6 , Polyunsaturated Alkamides , Alkaloids , Benzodioxoles/chemistry , Molecular Docking Simulation , Molecular Dynamics Simulation , Piperidines , Polyunsaturated Alkamides/metabolism
17.
Polim Med ; 52(1): 31-36, 2022.
Article En | MEDLINE | ID: mdl-35196422

Black pepper (Piper nigrum L.) is a climbing perennial plant in the Piperaceae family. Pepper has been known since antiquity for its use both as a medicine and a spice. It is particularly valued for its pungency attributed to its principal constituent - piperine. This review summarizes the information on the biological source of piperine, its extraction and isolation strategies, physicochemical properties, and pharmacological activity - analgesic, immunomodulatory, anti-depressive, anti-diarrheal, hepatoprotective, etc. The effect of piperine on biotransformation of co-administered drugs is also presented in this review, along with the mechanisms involved in its bioavailability-enhancing effect. Its important medicinal uses, including anti-hepatotoxic, anti-diarrheal, anti-depressive, analgesic, and immunomodulatory effects, besides many other traditional uses, are compiled. Based on an exhaustive review of literature, it may be concluded that piperine is a very promising alkaloid found in members of the Piperaceae family.


Alkaloids , Piper nigrum , Alkaloids/chemistry , Alkaloids/pharmacology , Alkaloids/therapeutic use , Benzodioxoles/chemistry , Benzodioxoles/pharmacology , Benzodioxoles/therapeutic use , Piper nigrum/chemistry , Piperidines/chemistry , Piperidines/pharmacology , Piperidines/therapeutic use , Polyunsaturated Alkamides/chemistry , Polyunsaturated Alkamides/pharmacology , Polyunsaturated Alkamides/therapeutic use
18.
J Med Chem ; 65(3): 2610-2622, 2022 02 10.
Article En | MEDLINE | ID: mdl-35067062

Upregulation of ATP binding cassette (ABC) transporter efflux pumps (i.e. P-glycoprotein, P-gp) can impart multidrug resistance, rendering many chemotherapeutics ineffective and seriously limiting treatment regimes. While ABC transporters remain an attractive target for therapeutic intervention, the development of clinically useful small-molecule inhibitors has proved challenging. In this report, we describe the structure-activity relationship (SAR) analysis of a newly discovered P-gp inhibitory pharmacophore, phenylpropanoid piperazine chrysosporazines, produced by co-isolated marine-derived fungi. In the absence of any total syntheses, we apply an innovative precursor-directed biosynthesis strategy that successfully repurposed fungal biosynthetic output, allowing us to isolate, characterize, and identify the structurally diverse neochrysosporazines A-Q. SAR analysis utilizing all known (and new) neochrysosporazines, chrysosporazines, and azachrysosporazines, plus semi-synthetic analogues, established the key structure requirements for the P-gp inhibitory pharmacophore, and, in addition, identified non-essential sites that allow for the design of affinity and other conjugated probes.


ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Benzodioxoles/pharmacology , Piperazines/pharmacology , Antineoplastic Agents/chemistry , Benzodioxoles/chemistry , Cell Line, Tumor , Chrysosporium/chemistry , Doxorubicin/pharmacology , Drug Resistance, Neoplasm/drug effects , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Piperazines/chemistry , Structure-Activity Relationship
19.
Biochem Biophys Res Commun ; 590: 158-162, 2022 01 29.
Article En | MEDLINE | ID: mdl-34974305

The progression of chronic kidney disease (CKD) increases the risks of cardiovascular morbidity and end-stage kidney disease. Indoxyl sulfate (IS), which is derived from dietary l-tryptophan by the action of bacterial l-tryptophan indole-lyase (TIL) in the gut, serves as a uremic toxin that exacerbates CKD-related kidney disorder. A mouse model previously showed that inhibition of TIL by 2-aza-l-tyrosine effectively reduced the plasma IS level, causing the recovery of renal damage. In this study, we found that (+)-sesamin and related lignans, which occur abundantly in sesame seeds, inhibit intestinal bacteria TILs. Kinetic studies revealed that (+)-sesamin and sesamol competitively inhibited Escherichia coli TIL (EcTIL) with Ki values of 7 µM and 14 µM, respectively. These Ki values were smaller than that of 2-aza-l-tyrosine (143 µM). Molecular docking simulation of (+)-sesamin- (or sesamol-)binding to EcTIL predicted that these inhibitors potentially bind near the active site of EcTIL, where the cofactor pyridoxal 5'-phosphate is bound, consistent with the kinetic results. (+)-Sesamin is a phytochemical with a long history of consumption and is generally regarded as safe. Hence, dietary supplementation of (+)-sesamin encapsulated in enteric capsules could be a promising mechanism-based strategy to prevent CKD progression. Moreover, the present findings would provide a new structural basis for designing more potent TIL inhibitors for the development of mechanism-based therapeutic drugs to treat CKD.


Dioxoles/pharmacology , Enzyme Inhibitors/pharmacology , Gastrointestinal Microbiome , Lignans/pharmacology , Renal Insufficiency, Chronic/enzymology , Renal Insufficiency, Chronic/etiology , Sesamum/chemistry , Tryptophanase/antagonists & inhibitors , Benzodioxoles/chemistry , Benzodioxoles/pharmacology , Dioxoles/chemistry , Gastrointestinal Microbiome/drug effects , Kinetics , Lignans/chemistry , Molecular Docking Simulation , Phenols/chemistry , Phenols/pharmacology , Tryptophanase/metabolism
20.
Cell ; 185(1): 158-168.e11, 2022 01 06.
Article En | MEDLINE | ID: mdl-34995514

Small molecule chaperones have been exploited as therapeutics for the hundreds of diseases caused by protein misfolding. The most successful examples are the CFTR correctors, which transformed cystic fibrosis therapy. These molecules revert folding defects of the ΔF508 mutant and are widely used to treat patients. To investigate the molecular mechanism of their action, we determined cryo-electron microscopy structures of CFTR in complex with the FDA-approved correctors lumacaftor or tezacaftor. Both drugs insert into a hydrophobic pocket in the first transmembrane domain (TMD1), linking together four helices that are thermodynamically unstable. Mutating residues at the binding site rendered ΔF508-CFTR insensitive to lumacaftor and tezacaftor, underscoring the functional significance of the structural discovery. These results support a mechanism in which the correctors stabilize TMD1 at an early stage of biogenesis, prevent its premature degradation, and thereby allosterically rescuing many disease-causing mutations.


Aminopyridines/metabolism , Benzodioxoles/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Indoles/metabolism , Protein Folding , Aminopyridines/chemistry , Aminopyridines/therapeutic use , Animals , Benzodioxoles/chemistry , Benzodioxoles/therapeutic use , Binding Sites , CHO Cells , Cell Membrane/chemistry , Cell Membrane/metabolism , Cricetulus , Cryoelectron Microscopy , Cystic Fibrosis/drug therapy , Cystic Fibrosis/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator/chemistry , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , HEK293 Cells , Humans , Hydrophobic and Hydrophilic Interactions , Indoles/chemistry , Indoles/therapeutic use , Molecular Chaperones/chemistry , Molecular Chaperones/metabolism , Molecular Chaperones/therapeutic use , Mutation , Protein Domains/genetics , Sf9 Cells , Transfection
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